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Formalisation of Selected Results from Group Theory

Joseph Johannes Thommes, Tobias Nipkow, Manuel Eberl
2021 Zenodo  
I extend and simplify a part of an already existing entry in the Archive of Formal Proofs that includes some theory about characters by Eberl [15] , by making use of the fundamental theorem of finitely  ... 
doi:10.5281/zenodo.4785363 fatcat:ggo4zojijrgk5kfuufsxxsfsgu

Verified Analysis of Random Binary Tree Structures

Manuel Eberl, Max W. Haslbeck, Tobias Nipkow
2020 Journal of automated reasoning  
B Manuel Eberl 1 Technische Universität Mönchen, 85748 Garching bei München, Germany r. t.  ...  A detailed explanation of this (especially in the context of Isabelle/HOL) can be found in an earlier paper by Eberl et al. [12] .  ... 
doi:10.1007/s10817-020-09545-0 fatcat:qoyl4mininf2fhowpcwtbwhj4q

A Verified Compiler for Probability Density Functions [chapter]

Manuel Eberl, Johannes Hölzl, Tobias Nipkow
2015 Lecture Notes in Computer Science  
Bhat et al. developed an inductive compiler that computes density functions for probability spaces described by programs in a simple probabilistic functional language. In this work, we implement such a compiler for a modified version of this language within the theorem prover Isabelle and give a formal proof of its soundness w.r.t. the semantics of the source and target language. Together with Isabelle's code generation for inductive predicates, this yields a fully verified, executable density
more » ... executable density compiler. The proof is done in two steps, using a standard refinement approach: first, an abstract compiler working with abstract functions modelled directly in the theorem prover's logic is defined and proven sound. Then, this compiler is refined to a concrete version that returns a target-language expression.
doi:10.1007/978-3-662-46669-8_4 fatcat:bu5tcxta5nh4tfc5tcqch5eb2a

Proving the Incompatibility of Efficiency and Strategyproofness via SMT Solving

Florian Brandl, Felix Brandt, Manuel Eberl, Christian Geist
2018 Journal of the ACM  
The authors also thank Manuel Eberl for the extensive verification work in Isabelle/HOL, Alberto Griggio and Mohammad Mehdi Pourhashem Kallehbasti for guidance on how to most effectively use MathSAT and  ... 
doi:10.1145/3125642 fatcat:psgz7zepnnaslal6bnuhpwqkmq

A Decision Procedure for Univariate Real Polynomials in Isabelle/HOL

Manuel Eberl
2015 Proceedings of the 2015 Conference on Certified Programs and Proofs - CPP '15  
Sturm sequences are a method for computing the number of real roots of a univariate real polynomial inside a given interval efficiently. In this paper, this fact and a number of methods to construct Sturm sequences efficiently have been formalised with the interactive theorem prover Isabelle/HOL. Building upon this, an Isabelle/HOL proof method was then implemented to prove interesting statements about the number of real roots of a univariate real polynomial and related properties such as
more » ... rties such as non-negativity and monotonicity.
doi:10.1145/2676724.2693166 dblp:conf/cpp/Eberl15 fatcat:ofuh7d52wfbr5bnoyj2steyuwa

High Confidence Prediction of Essential Genes in Burkholderia Cenocepacia

Mario Juhas, Manuel Stark, Christian von Mering, Puthapoom Lumjiaktase, Derrick W. Crook, Miguel A. Valvano, Leo Eberl, John R. Battista
2012 PLoS ONE  
Essential genes are absolutely required for the survival of an organism. The identification of essential genes, besides being one of the most fundamental questions in biology, is also of interest for the emerging science of synthetic biology and for the development of novel antimicrobials. New antimicrobial therapies are desperately needed to treat multidrug-resistant pathogens, such as members of the Burkholderia cepacia complex.
doi:10.1371/journal.pone.0040064 pmid:22768221 pmcid:PMC3386938 fatcat:vz3ahnxevjd4vljd6yc6by4crq

Positive selection of ORF3a and ORF8 genes drives the evolution of SARS-CoV-2 during the 2020 COVID-19 pandemic [article]

Lauro Velazquez-Salinas, Selene Zarate, Samantha Eberl, Douglas P Gladue, Isabel Novella, Manuel V Borca
2020 bioRxiv   pre-print
In this study, we analyzed full-length SARS-CoV-2 genomes from multiple countries to determine early trends in the evolutionary dynamics of the novel COVID-19 pandemic. Results indicated SARS-CoV-2 evolved early into at least three phylogenetic groups, characterized by positive selection at specific residues of the accessory proteins OFR3a and ORF8a. We also report evidence of epistatic interactions among sites in the genome that may be important in the generation of variants adapted to humans.
more » ... adapted to humans. These observations might impact not only public health, but also suggest more studies are needed to understand the genetic mechanisms that may affect the development of therapeutic and preventive tools, like antivirals and vaccines.
doi:10.1101/2020.04.10.035964 fatcat:3mtnw6tmvnhhla42cm443myfnq

Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells

Maria A. Johansson, Sophia Björkander, Manuel Mata Forsberg, Khaleda Rahman Qazi, Maria Salvany Celades, Julia Bittmann, Matthias Eberl, Eva Sverremark-Ekström
2016 Frontiers in Immunology  
Copyright © 2016 Johansson, Björkander, Mata Forsberg, Qazi, Salvany Celades, Bittmann, Eberl and Sverremark-Ekström.  ... 
doi:10.3389/fimmu.2016.00273 pmid:27462316 pmcid:PMC4939411 fatcat:tqviwun4f5dltiyxt2hbqtjsmi

Proving the Incompatibility of Efficiency and Strategyproofness via SMT Solving [article]

Florian Brandl, Felix Brandt, Manuel Eberl, Christian Geist
2017 arXiv   pre-print
Eberl. 2016a. A Formal Proof of the Incompatibility of SD-Efficiency and SD-Strategy-Proofness. Bachelor's thesis. Technische Universität München. M. Eberl. 2016b.  ...  This proof is essentially a paraphrased version of the formal Isabelle/HOL proof, which is available in the AFP entry [Eberl 2016b].  ... 
arXiv:1604.05692v4 fatcat:ixsi7gcfenexniafwl74qth5wa

Positive Selection of ORF1ab, ORF3a, and ORF8 Genes Drives the Early Evolutionary Trends of SARS-CoV-2 During the 2020 COVID-19 Pandemic

Lauro Velazquez-Salinas, Selene Zarate, Samantha Eberl, Douglas P. Gladue, Isabel Novella, Manuel V. Borca
2020 Frontiers in Microbiology  
In this study, we analyzed full-length SARS-CoV-2 genomes from multiple countries to determine early trends in the evolutionary dynamics of the novel COVID-19 pandemic. Results indicated SARS-CoV-2 evolved early into at least three phylogenetic groups, characterized by positive selection at specific residues of the accessory proteins ORF3a and ORF8. Also, we are reporting potential relevant sites under positive selection at specific sites of non-structural proteins nsp6 and helicase. Our
more » ... elicase. Our analysis of co-evolution showed evidence of epistatic interactions among sites in the genome that may be important in the generation of variants adapted to humans. These observations might impact not only public health but also suggest that more studies are needed to understand the genetic mechanisms that may affect the development of therapeutic and preventive tools, like antivirals and vaccines. Collectively, our results highlight the identification of ongoing selection even in a scenario of conserved sequences collected over the first 3 months of this pandemic.
doi:10.3389/fmicb.2020.550674 pmid:33193132 pmcid:PMC7644918 fatcat:3zroeao2qnhgpmacn2ac5jwnqe

Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner

Manuel Coutaz, Benjamin P. Hurrell, Floriane Auderset, Haiping Wang, Stefanie Siegert, Gerard Eberl, Ping-Chih Ho, Freddy Radtke, Fabienne Tacchini-Cottier
2016 Scientific Reports  
Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with
more » ... tant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function.
doi:10.1038/srep39117 pmid:27974744 pmcid:PMC5156918 fatcat:eeha73idvvcfhfkl3sa5vmgxza

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

Peter Matzneller, Manuel Kussmann, Sabine Eberl, Alexandra Maier-Salamon, Walter Jäger, Martin Bauer, Oliver Langer, Markus Zeitlinger, Wolfgang Poeppl
2018 European journal of drug metabolism and pharmacokinetics  
and objective P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood-brain barrier, restricts the distribution of diverse central nervous systemtargeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which
more » ... avenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration. Methods Two different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. Results In contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. Conclusion The present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound. Key Points This study investigated the pharmacokinetics of tariquidar in rats after oral, intraperitoneal and intravenous administration. Out of two tariquidar formulations used, a microemulsion showed significantly higher oral bioavailability in rats and might be considered for further testing. Availability of a tariquidar formulation with good oral bioavailability in humans would allow for a broader use of the drug in clinical research as a booster of brain delivery of P-gp substrate drugs. Wolfgang Poeppl and Markus Zeitlinger are shared senior authors of this manuscript.
doi:10.1007/s13318-018-0474-x pmid:29616423 fatcat:c7ta44vwzzg4vh5c3fmcevrpdm

Functional Relevance of the Switch of VEGF Receptors/Co-Receptors during Peritoneal Dialysis-Induced Mesothelial to Mesenchymal Transition

María Luisa Pérez-Lozano, Pilar Sandoval, Ángela Rynne-Vidal, Abelardo Aguilera, José Antonio Jiménez-Heffernan, Patricia Albar-Vizcaíno, Pedro L. Majano, José Antonio Sánchez-Tomero, Rafael Selgas, Manuel López-Cabrera, Matthias Eberl
2013 PLoS ONE  
Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/ VEGFRs/co-receptors axis
more » ... co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-b1 plus IL-1b (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the coreceptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGF.
doi:10.1371/journal.pone.0060776 pmid:23585849 pmcid:PMC3621952 fatcat:axijzkhbobfq7ont762ywwjbva

Biomarker research to improve clinical outcomes of peritoneal dialysis: consensus of the European Training and Research in Peritoneal Dialysis (EuTRiPD) network

Christoph Aufricht, Robert Beelen, Matthias Eberl, Michel Fischbach, Donald Fraser, Achim Jörres, Klaus Kratochwill, Manuel LópezCabrera, Peter Rutherford, Claus-Peter Schmitt, Nicholas Topley, Janusz Witowski
2017 Kidney International  
Peritoneal dialysis therapy (PD) has a substantial need for biomarker as tools to identify patients that are at highest risk for PD-related complications and to guide personalised interventions that may improve clinical outcome in the individual patient. In this consensus paper, members of the European Training and Research in Peritoneal Dialysis Network (EuTRiPD) review the current status of biomarker research in PD and suggest a selection of biomarkers that might become relevant for the care
more » ... evant for the care of PD patients and which is directly accessible in PD effluents. Currently used biomarkers collected in a Delphi procedure were first triaged for inclusion as surrogate endpoints for a clinical trial (IL-6, IL-8, ex-vivo stimulated IL-6 release, CA-125, AOPP). Next, novel biomarkers were selected as promising candidates for proof-of-concept studies, and differentiated into inflammation-signature (including IL-17, M 1 /M 2 , T reg /Th17), MMT-signature (including miR-21, miR-31) as well as signatures for senescence and inadequate cellular stress responses. Finally, the need to define pathogen-specific immune fingerprints and phenotype associated molecular signatures (PAMS) utilizing effluents from clinical cohorts of PD patients, and 'omics technologies and bioinformatics/biostatistics was expressed as need for future joint research efforts. Biomarker research in PD offers the potential to develop valuable tools to improve patient management. However, for all biomarkers discussed in this consensus paper, the association of biological rationales to relevant clinical outcomes remains to be rigorously validated in adequately powered, prospective independent clinical studies.
doi:10.1016/j.kint.2017.02.037 pmid:28797473 fatcat:6spxjcrlnnfdtjlltlighppuva

A formal proof of the Incompatibility of SD-Efficiency and SD-Strategy-Proofness

Manuel Eberl
In the design of voting rules, there are three intuitively desirable properties that one might reasonably expect such a rule to fulfil: • A voting rule should treat every voter and any alternative on the ballot equally. • The result should satisfy the voters as far as possible; i. e. there should be no other result that is obviously better for everyone. • No voter should be able to obtain an advantage by lying about her preferences. These intuitively desirable properties have formal
more » ... formal counterparts by the name of Anonymity and Neutrality, Efficiency, and Strategy-Proofness, respectively. It is well-known that the last two are in some way in conflict to one another -fulfilling both of them is often not possible or imposes great restrictions. This work focuses on the setting of randomised voting with weak preferences (i. e. voters may submit preferences with ties), particularly on previous work by Brandl et al., who used computerised search and SMT solvers to prove a conjecture by Aziz et al. that no anonymous and neutral randomised voting rule (known as Social Decision Scheme) can fulfil the notions of both SD-Efficiency and SD-Strategy-Proofness. My work consists of a fully mechanised formal proof of this result using the interactive theorem prover Isabelle and, based upon this, a human-readable pen-and-paper proof. iv Imposing There is one alternative which can never win, no matter what the voters do. Manipulable There is at least one situation where a voter has an incentive to lie. Randomisation is an obvious way that one may consider to solve this problem: if half of the voters prefer a and the others prefer b, one can simply toss a coin to resolve the tie. Unfortunately, randomisation does not solve all problems. As Gibbard [Gib77; Nan98] has also shown: if one demands, quite reasonably, that voting rules be anonymous (i. e. they treat all voters the same), then the only SDS that satisfies ex-post-Efficiency (a relatively weak kind of efficiency) and something known as strong SD-Strategy-Proofness is the rule of Random Dictatorship. This rule chooses a voter uniformly at random and decides that that voter's most-preferred alternative wins. This shows that even in the randomised setting, Efficiency and Strategy-Proofness are difficult to combine. In this result by Gibbard, voters are required to have linear ballots, i. e. they need to submit their preferences as a list in order of decreasing preference with no ties allowed. In this work, we shall consider a more liberal setting where ties are allowed. The goal is to prove a conjecture by Aziz et al.: that any anonymous and neutral SDS (i. e. that treats all voters and alternatives equally) in this setting violates either SD-Strategy-Proofness or SD-Efficiency. SD, in this context, stands for Stochastic Dominance, which is one particular way to define • using the interactive theorem prover Isabelle to develop a fully machine-checked version of the entire proof, including the parts previously done by the Java program, the SMT solver, and informal pen-and-paper reasoning. • developing a 'human-readable' version of the SMT proof, i. e. a proof that is both detailed and structured enough to enable a human to verify the validity of each step. Both of these goals were achieved, and the formal Isabelle/HOL proof of the impossibility result [Ebe16b] and the required definitions and facts about Social Choice Theory [Ebe16a] are available in the Archive of Formal Proofs, which is a peer-reviewed repository of Isabelle/ HOL proof developments that is continuously maintained by the Isabelle developers to ensure compatibility with future Isabelle releases despite the extensive changes to the infrastructure and the background theory with every new Isabelle release. Main Impossibility Result Example 4. Consider the following two preference profiles: R : {b, d}, {a, c} {c, d}, {a, b} a, b, {c, d} a, c, {b, d} R : {a, b}, {c, d} {a, c}, {b, d} d, {a, b}, c d, c, {a, b} If Agent 4 in R replaces her preferences with a, {c, d}, b, we obtain the following profile: {b, d}, {a, c} {c, d}, {a, b} a, b, {c, d} a, {c, d}, b On the other hand, renaming the alternatives in R with σ = (a d)(b c) yields the following profile:
doi:10.14459/2016md1485242 fatcat:cokomapajbgj3imaqa62smc6dq
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