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Book ; Online: Adaptive Decision-Making with Constraints and Dependent Losses

Muehlebach, Michael

Performance Guarantees and Applications to Online and Nonlinear Identification

2023

Abstract: We consider adaptive decision-making problems where an agent optimizes a cumulative performance objective by repeatedly choosing among a finite set of options. Compared to the classical prediction-with-expert-advice set-up, we consider situations where ... ...

Abstract	We consider adaptive decision-making problems where an agent optimizes a cumulative performance objective by repeatedly choosing among a finite set of options. Compared to the classical prediction-with-expert-advice set-up, we consider situations where losses are constrained and derive algorithms that exploit the additional structure in optimal and computationally efficient ways. Our algorithm and our analysis is instance dependent, that is, suboptimal choices of the environment are exploited and reflected in our regret bounds. The constraints handle general dependencies between losses (even across time), and are flexible enough to also account for a loss budget, which the environment is not allowed to exceed. The performance of the resulting algorithms is highlighted in two numerical examples, which include a nonlinear and online system identification task. Comment: 8 pages
Keywords	Computer Science - Machine Learning ; Electrical Engineering and Systems Science - Systems and Control
Subject code	006
Publishing date	2023-04-06
Publishing country	us
Document type	Book ; Online
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Article ; Online: Concentrating all helper protein functions on a single entity allows rescue of recombinant measles virus by transfection of just two plasmids.

Auste, Arne / Mühlebach, Michael D

The Journal of general virology

2023 Volume 103, Issue 11

Abstract: The generation of recombinant measles virus (MeV) from manipulated genomes on plasmid DNA is quite a complex and inefficient process. As a member of the ... ...

Abstract	The generation of recombinant measles virus (MeV) from manipulated genomes on plasmid DNA is quite a complex and inefficient process. As a member of the order
MeSH term(s)	Animals ; Measles virus/genetics ; Transfection ; Plasmids/genetics ; Virus Replication/genetics ; RNA, Viral/genetics ; Genome, Viral
Chemical Substances	RNA, Viral
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001815
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Article ; Online: Measles virus in cancer therapy.

Mühlebach, Michael D

Current opinion in virology

2020 Volume 41, Page(s) 85–97

Abstract: Over the last years, the development of viruses to treat cancer patients has re-gained considerable attention. A genetically modified herpesvirus, Talimogene laherparepvec, has already been authorized for the treatment of melanoma patients. Also ... ...

Abstract	Over the last years, the development of viruses to treat cancer patients has re-gained considerable attention. A genetically modified herpesvirus, Talimogene laherparepvec, has already been authorized for the treatment of melanoma patients. Also recombinant measles virus (MeV) is developed as an oncolytic virus. Because of its high genetic flexibility, a number of different MeV strains have been the basis for the generation of targeted, armed, or shielded viruses that are highly specific for a given tumor target, more effective, or protected against serum neutralization. Such MeV have been extensively tested in vitro and in vivo, whereby remarkable oncolytic potency is accompanied by safety also in non-human primates. Therefore, MeV has been introduced into 19 different clinical trials and has reached phase II against two different tumor entities, multiple myeloma and ovarian carcinoma. Remarkably, one patient with advanced stage myeloma experienced long-term remission after treatment, visualizing the potency of this approach.
MeSH term(s)	Animals ; Humans ; Measles virus/genetics ; Measles virus/physiology ; Melanoma/therapy ; Melanoma/virology ; Oncolytic Virotherapy ; Oncolytic Viruses/genetics ; Oncolytic Viruses/physiology
Language	English
Publishing date	2020-08-28
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2020.07.016
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Book ; Online: Accelerated First-Order Optimization under Nonlinear Constraints

Muehlebach, Michael / Jordan, Michael I.

2023

Abstract: We exploit analogies between first-order algorithms for constrained optimization and non-smooth dynamical systems to design a new class of accelerated first-order algorithms for constrained optimization. Unlike Frank-Wolfe or projected gradients, these ... ...

Abstract	We exploit analogies between first-order algorithms for constrained optimization and non-smooth dynamical systems to design a new class of accelerated first-order algorithms for constrained optimization. Unlike Frank-Wolfe or projected gradients, these algorithms avoid optimization over the entire feasible set at each iteration. We prove convergence to stationary points even in a nonconvex setting and we derive accelerated rates for the convex setting both in continuous time, as well as in discrete time. An important property of these algorithms is that constraints are expressed in terms of velocities instead of positions, which naturally leads to sparse, local and convex approximations of the feasible set (even if the feasible set is nonconvex). Thus, the complexity tends to grow mildly in the number of decision variables and in the number of constraints, which makes the algorithms suitable for machine learning applications. We apply our algorithms to a compressed sensing and a sparse regression problem, showing that we can treat nonconvex $\ell^p$ constraints ($p<1$) efficiently, while recovering state-of-the-art performance for $p=1$. Comment: 44 pages, 6 figures
Keywords	Mathematics - Optimization and Control ; Computer Science - Machine Learning ; Electrical Engineering and Systems Science - Signal Processing ; Statistics - Machine Learning
Subject code	006
Publishing date	2023-02-01
Publishing country	us
Document type	Book ; Online
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Article: Das Masernvirus im Fokus – von wirksamen und sicheren Impfstoffen über Krebstherapie bis hin zum Gentransfer

Muehlebach, Michael / Buchholz, Christian / Götz, Karen Brigitta

Bulletin zur Arzneimittelsicherheit, 2011(4):20-23

2011

Abstract: Gleich mehrere Fachgebiete beziehungsweise Arbeitsgruppen im Paul-Ehrlich-Institut (PEI) beschäftigen sich mit Masernviren. Die Abteilung Virologie betreut die Zulassungsverfahren sowie die zugelassenen Virusimpfstoffe und prüft die Impfstoffchargen. ... ...

Institution	Paul-Ehrlich-Institut
Abstract	Gleich mehrere Fachgebiete beziehungsweise Arbeitsgruppen im Paul-Ehrlich-Institut (PEI) beschäftigen sich mit Masernviren. Die Abteilung Virologie betreut die Zulassungsverfahren sowie die zugelassenen Virusimpfstoffe und prüft die Impfstoffchargen. Zwei Forschungsgruppen in der bis 2011 von Prof. Cichutek geleiteten Abteilung „Medizinische Biotechnologie“ haben Masernviren unter verwandten Gesichtspunkten im Fokus. Forscher um Prof. Christian Buchholz, Fachgebiet „Virale Gentransfer-Arzneimittel“, forschen an Veränderungen der Hüllproteine des Masernvirus, damit sie für den hochselektiven Gentransfer genutzt werden können. Zudem erforschen sie – wie auch Mitarbeiter der Forschungsgruppe „Onkolytische Masernviren und Impfvektoren“ um Dr. Michael Mühlebach – das Virus intensiv im Hinblick auf seine Nutzbarkeit für die Krebstherapie. Im Rahmen einer internationalen Forschungskooperation haben Mühlebach und Kollegen kürzlich aufgeklärt, wie Masernviren in Epithelien gelangen, von wo aus sie über die Atemwege ausgeschieden werden und erneut Menschen infizieren können. Diese Erkenntnis kann möglicherweise auch dazu beitragen, die Effizienz von Masernviren als onkolytische Viren in der Krebstherapie besser abschätzen zu können. Über die Forschungsergebnisse berichtete Nature in seiner Vorab-Onlineausgabe vom 2. November 2011.1 Im Folgenden werden einige PEI-Forschungsaktivitäten zu Masernviren vorgestellt.
Keywords	Masernvirus
Language	German
Document type	Article
DOI	10.4126/FRL01-006412485
Database	Repository for Life Sciences

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Article ; Online: Vaccine platform recombinant measles virus.

Mühlebach, Michael D

Virus genes

2017 Volume 53, Issue 5, Page(s) 733–740

Abstract: The classic development of vaccines is lengthy, tedious, and may not necessarily be successful as demonstrated by the case of HIV. This is especially a problem for emerging pathogens that are newly introduced into the human population and carry the ... ...

Abstract	The classic development of vaccines is lengthy, tedious, and may not necessarily be successful as demonstrated by the case of HIV. This is especially a problem for emerging pathogens that are newly introduced into the human population and carry the inherent risk of pandemic spread in a naïve population. For such situations, a considerable number of different platform technologies are under development. These are also under development for pathogens, where directly derived vaccines are regarded as too complicated or even dangerous due to the induction of inefficient or unwanted immune responses causing considerable side-effects as for dengue virus. Among platform technologies are plasmid-based DNA vaccines, RNA replicons, single-round infectious vector particles, or replicating vaccine-based vectors encoding (a) critical antigen(s) of the target pathogens. Among the latter, recombinant measles viruses derived from vaccine strains have been tested. Measles vaccines are among the most effective and safest life-attenuated vaccines known. Therefore, the development of Schwarz-, Moraten-, or AIK-C-strain derived recombinant vaccines against a wide range of mostly viral, but also bacterial pathogens was quite straightforward. These vaccines generally induce powerful humoral and cellular immune responses in appropriate animal models, i.e., transgenic mice or non-human primates. Also in the recent first clinical phase I trial, the results have been quite encouraging. The trial indicated the expected safety and efficacy also in human patients, interestingly independent from the level of prevalent anti-measles immunity before the trial. Thereby, recombinant measles vaccines expressing additional antigens are a promising platform for future vaccines.
MeSH term(s)	Animals ; Humans ; Measles/immunology ; Measles/prevention & control ; Measles Vaccine/immunology ; Measles virus/immunology ; Vaccines, Attenuated/immunology ; Vaccines, Synthetic/immunology ; Viral Vaccines/immunology
Chemical Substances	Measles Vaccine ; Vaccines, Attenuated ; Vaccines, Synthetic ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2017-07-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639496-6
ISSN	1572-994X ; 0920-8569
ISSN (online)	1572-994X
ISSN	0920-8569
DOI	10.1007/s11262-017-1486-3
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Article ; Online: Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines.

Ebenig, Aileen / Lange, Mona V / Mühlebach, Michael D

NPJ vaccines

2022 Volume 7, Issue 1, Page(s) 119

Abstract: Live-attenuated measles virus (MeV) has been extraordinarily effective in preventing measles infections and their often deadly sequelae, accompanied by remarkable safety and stability since their first licensing in 1963. The advent of recombinant DNA ... ...

Abstract	Live-attenuated measles virus (MeV) has been extraordinarily effective in preventing measles infections and their often deadly sequelae, accompanied by remarkable safety and stability since their first licensing in 1963. The advent of recombinant DNA technologies, combined with systems to generate infectious negative-strand RNA viruses on the basis of viral genomes encoded on plasmid DNA in the 1990s, paved the way to generate recombinant, vaccine strain-derived MeVs. These live-attenuated vaccine constructs can encode and express additional foreign antigens during transient virus replication following immunization. Effective humoral and cellular immune responses are induced not only against the MeV vector, but also against the foreign antigen cargo in immunized individuals, which can protect against the associated pathogen. This review aims to present an overview of the versatility of this vaccine vector as platform technology to target various diseases, as well as current research and developmental stages, with one vaccine candidate ready to enter phase III clinical trials to gain marketing authorization, MV-CHIK.
Language	English
Publishing date	2022-10-15
Publishing country	England
Document type	Journal Article ; Review
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-022-00543-4
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Book ; Online: Online Learning under Adversarial Nonlinear Constraints

Kolev, Pavel / Martius, Georg / Muehlebach, Michael

2023

Abstract: In many applications, learning systems are required to process continuous non-stationary data streams. We study this problem in an online learning framework and propose an algorithm that can deal with adversarial time-varying and nonlinear constraints. ... ...

Abstract	In many applications, learning systems are required to process continuous non-stationary data streams. We study this problem in an online learning framework and propose an algorithm that can deal with adversarial time-varying and nonlinear constraints. As we show in our work, the algorithm called Constraint Violation Velocity Projection (CVV-Pro) achieves $\sqrt{T}$ regret and converges to the feasible set at a rate of $1/\sqrt{T}$, despite the fact that the feasible set is slowly time-varying and a priori unknown to the learner. CVV-Pro only relies on local sparse linear approximations of the feasible set and therefore avoids optimizing over the entire set at each iteration, which is in sharp contrast to projected gradients or Frank-Wolfe methods. We also empirically evaluate our algorithm on two-player games, where the players are subjected to a shared constraint. Comment: NeurIPS 2023
Keywords	Computer Science - Machine Learning ; Mathematics - Optimization and Control
Subject code	006
Publishing date	2023-06-06
Publishing country	us
Document type	Book ; Online
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Book ; Online: On Constraints in First-Order Optimization

Muehlebach, Michael / Jordan, Michael I.

A View from Non-Smooth Dynamical Systems

2021

Abstract: We introduce a class of first-order methods for smooth constrained optimization that are based on an analogy to non-smooth dynamical systems. Two distinctive features of our approach are that (i) projections or optimizations over the entire feasible set ... ...

Abstract	We introduce a class of first-order methods for smooth constrained optimization that are based on an analogy to non-smooth dynamical systems. Two distinctive features of our approach are that (i) projections or optimizations over the entire feasible set are avoided, in stark contrast to projected gradient methods or the Frank-Wolfe method, and (ii) iterates are allowed to become infeasible, which differs from active set or feasible direction methods, where the descent motion stops as soon as a new constraint is encountered. The resulting algorithmic procedure is simple to implement even when constraints are nonlinear, and is suitable for large-scale constrained optimization problems in which the feasible set fails to have a simple structure. The key underlying idea is that constraints are expressed in terms of velocities instead of positions, which has the algorithmic consequence that optimizations over feasible sets at each iteration are replaced with optimizations over local, sparse convex approximations. In particular, this means that at each iteration only constraints that are violated are taken into account. The result is a simplified suite of algorithms and an expanded range of possible applications in machine learning. Comment: 46 pages, 11 figures
Keywords	Mathematics - Optimization and Control ; Computer Science - Machine Learning ; Electrical Engineering and Systems Science - Systems and Control
Subject code	510
Publishing date	2021-07-17
Publishing country	us
Document type	Book ; Online
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Article ; Online: Development of Entry-Targeted Oncolytic Measles Viruses.

Mühlebach, Michael D / Cattaneo, Roberto

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2058, Page(s) 51–75

Abstract: This chapter describes the development of recombinant oncolytic measles viruses (MeV) that selectively enter and destroy tumor cells. The envelope of MeV is a favorable targeting substrate because receptor attachment and membrane fusion functions are ... ...

Abstract	This chapter describes the development of recombinant oncolytic measles viruses (MeV) that selectively enter and destroy tumor cells. The envelope of MeV is a favorable targeting substrate because receptor attachment and membrane fusion functions are separated on two proteins: the hemagglutinin (H) that binds receptors, and the fusion (F) protein that fuses the viral envelope with the cell membrane. The cell entry process, which depends on receptor recognition and occurs at the plasma membrane at neutral pH, results in the delivery of encapsidated genomes to the cytoplasm, where they replicate. Towards improving cancer specificity of oncolytic MeV, two types of cell entry targeting have been achieved. First, entry has been redirected through cancer-specific cell surface proteins. This was done by displaying specificity domains on H while also ablating binding to its natural receptors. Second, activation of the F protein was made dependent on secreted cancer proteases, while also interfering with F cleavage/activation by a ubiquitous intracellular protease. This chapter describes how entry-targeted MeV are produced: In short, gene cassettes with modified H or F coding regions are generated, and then introduced into the viral genome available on plasmid DNA. Such full-length genome plasmids are transfected in cell lines expressing, stably or transiently, the three viral proteins necessary for genome replication. Infectious centers form among these "rescue" cells, which allow isolation of clonal recombinant viruses. These are amplified, characterized in vitro, and then evaluated for their oncolytic activity in appropriate preclinical animal models.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Cloning, Molecular ; Gene Expression ; Gene Order ; Genetic Engineering/methods ; Genetic Vectors/genetics ; HEK293 Cells ; Humans ; Measles virus/genetics ; Mice ; Oncolytic Viruses/genetics ; Plasmids/genetics ; Receptors, Virus/metabolism ; Vero Cells ; Virus Attachment ; Virus Internalization
Chemical Substances	Receptors, Virus
Language	English
Publishing date	2019-09-04
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9794-7_4
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