The development of bioinformatics workflows to explore single-cell multi-omics data from T and B lymphocytes

The adaptive immune response is responsible for recognising, containing and eliminating viral infection, and protecting from further reinfection. This antigen-specific response is driven by T and B cells, which recognise antigenic epitopes via highly specific heterodimeric surface receptors, termed T-cell receptors (TCRs) and B cell receptors (BCRs). The theoretical diversity of the receptor repertoire that can be generated via homologous recombination of V, D and J genes is large enough (>1015 unique sequences) that virtually any antigen can be recognised. However, only a subset of these are generated within the human body, and how they succeed in specifically recognising any pathogen(s) and distinguishing these from self-proteins remains largely unresolved. The recent advances in applying single-cell genomics technologies to simultaneously measure the clonality, surface phenotype and transcriptomic signature of pathogen- specific immune cells have significantly improved understanding of these questions. Single-cell multi-omics permits the accurate identification of clonally expanded populations, their differentiation trajectories, the level of immune receptor repertoire diversity involved in the response and the phenotypic and molecular heterogeneity. This thesis aims to develop a bioinformatic workflow utilising single-cell multi-omics data to explore, quantify and predict the clonal and transcriptomic signatures of the human T-cell response during and following viral infection. In the first aim, a web application, VDJView, was developed to facilitate the simultaneous analysis and visualisation of clonal, transcriptomic and clinical metadata of T and B cell multi-omics data. The application permits non-bioinformaticians to perform quality control and common analyses of single-cell genomics data integrated with other metadata, thus permitting the identification of biologically and clinically relevant parameters. The second aim pertains to analysing the functional, molecular and immune receptor profiles of CD8+ T cells in the acute phase of primary hepatitis C virus (HCV) infection. This analysis identified a novel population of progenitors of exhausted T cells, and lineage tracing revealed distinct trajectories with multiple fates and evolutionary plasticity. Furthermore, it was observed that high-magnitude IFN-γ CD8+ T-cell response is associated with the increased probability of viral escape and chronic infection. Finally, in the third aim, a novel analysis is presented based on the topological characteristics of a network generated on pathogen-specific, paired-chain, CD8+ TCRs. This analysis revealed how some cross-reactivity between TCRs can be explained via the sequence similarity between TCRs and that this property is not uniformly distributed across all pathogen-specific TCR repertoires. Strong correlations between the topological properties of the network and the biological properties of the TCR sequences were identified and highlighted. The suite of workflows and methods presented in this thesis are designed to be adaptable to various T and B cell multi-omic datasets. The associated analyses contribute to understanding the role of T and B cells in the adaptive immune response to viral-infection and cancer

Asynchronous Computation of Tube-based Model Predictive Control

Tube-based model predictive control (MPC) methods bound deviations from a nominal trajectory due to uncertainties in order to ensure constraint satisfaction. While techniques that compute the tubes online reduce conservativeness and increase performance, they suffer from high and potentially prohibitive computational complexity. This paper presents an asynchronous computation mechanism for system level tube-MPC (SLTMPC), a recently proposed tube-based MPC method which optimizes over both the nominal trajectory and the tubes. Computations are split into a primary and a secondary process, computing the nominal trajectory and the tubes, respectively. This enables running the primary process at a high frequency and moving the computationally complex tube computations to the secondary process. We show that the secondary process can continuously update the tubes, while retaining recursive feasibility and robust stability of the primary process.Comment: Submitted to IFAC WC 202

Robust Optimal Control for Nonlinear Systems with Parametric Uncertainties via System Level Synthesis

This paper addresses the problem of optimally controlling nonlinear systems with norm-bounded disturbances and parametric uncertainties while robustly satisfying constraints. The proposed approach jointly optimizes a nominal nonlinear trajectory and an error feedback, requiring minimal offline design effort and offering low conservatism. This is achieved by decomposing the affine-in-the-parameter uncertain nonlinear system into a nominal $\textit{nonlinear}$ system and an uncertain linear time-varying system. Using this decomposition, we can apply established tools from system level synthesis to $\textit{convexly}$ over-bound all uncertainties in the nonlinear optimization problem. Moreover, it enables tight joint optimization of the linearization error bounds, parametric uncertainties bounds, nonlinear trajectory, and error feedback. With this novel controller parameterization, we can formulate a convex constraint to ensure robust performance guarantees for the nonlinear system. The presented method is relevant for numerous applications related to trajectory optimization, e.g., in robotics and aerospace engineering. We demonstrate the performance of the approach and its low conservatism through the simulation example of a post-capture satellite stabilization.Comment: Accepted for CDC (Singapore, 13-15 December 2023). Code: https://gitlab.ethz.ch/ics/nonlinear-parametric-SL

Galaxy-scale Star Formation on the Red Sequence: the Continued Growth of S0s and the Quiescence of Ellipticals

This paper examines star formation (SF) in relatively massive, primarily early-type galaxies (ETGs) at z~0.1. A sample is drawn from bulge-dominated GALEX/SDSS galaxies on the optical red sequence with strong UV excess and yet quiescent SDSS spectra. High-resolution far-UV imaging of 27 such ETGs using HST ACS/SBC reveals structured UV morphology in 93% of the sample, consistent with low-level ongoing SF (~0.5 Ms/yr). In 3/4 of the sample the SF is extended on galaxy scales (25-75 kpc), while the rest contains smaller (5-15 kpc) SF patches in the vicinity of an ETG - presumably gas-rich satellites being disrupted. Optical imaging reveals that all ETGs with galaxy-scale SF in our sample have old stellar disks (mostly S0 type). None is classified as a true elliptical. In our sample, galaxy-scale SF takes the form of UV rings of varying sizes and morphologies. For the majority of such objects we conclude that the gas needed to fuel current SF has been accreted from the IGM, probably in a prolonged, quasi-static manner, leading in some cases to additional disk buildup. The remaining ETGs with galaxy-scale SF have UV and optical morphologies consistent with minor merger-driven SF or with the final stages of SF in fading spirals. Our analysis excludes that all recent SF on the red sequence resulted from gas-rich mergers. We find further evidence that galaxy-scale SF is almost exclusively an S0 phenomenon (~20% S0s have SF) by examining the overall optically red SDSS ETGs. Conclusion is that significant number of field S0s maintain or resume low-level SF because the preventive feedback is not in place or is intermittent. True ellipticals, on the other hand, stay entirely quiescent even in the field.Comment: Accepted for publication in ApJ. Contains color figures, but compatible with non-color printer

The Great Debate at \u27Immunotherapy Bridge\u27, Naples, December 5, 2019.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report

VDJdb in 2019: database extension, new analysis infrastructure and a T-cell receptor motif compendium

Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold. Furthermore, several new analysis methods are included. For example, batch annotation of TCR repertoire sequencing samples allows for annotating large datasets on-line. Using recently developed bioinformatic methods for TCR motif mining, we have built a reduced set of high-quality TCR motifs that can be used for both training TCR specificity predictors and matching against TCRs of interest. These additions enhance the versatility of the VDJdb in the task of exploring T-cell antigen specificities. The database is available at https://vdjdb.cdr3.net

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles