(Metric) Bisimulation Games and Real-Valued Modal Logics for Coalgebras

Behavioural equivalences can be characterized via bisimulations, modal logics and spoiler-defender games. In this paper we review these three perspectives in a coalgebraic setting, which allows us to generalize from the particular branching type of a transition system. We are interested in qualitative notions (classical bisimulation) as well as quantitative notions (bisimulation metrics). Our first contribution is to introduce a spoiler-defender bisimulation game for coalgebras in the classical case. Second, we introduce such games for the metric case and furthermore define a real-valued modal coalgebraic logic, from which we can derive the strategy of the spoiler. For this logic we show a quantitative version of the Hennessy-Milner theorem

Fixpoint Games on Continuous Lattices

Many analysis and verifications tasks, such as static program analyses and model-checking for temporal logics reduce to the solution of systems of equations over suitable lattices. Inspired by recent work on lattice-theoretic progress measures, we develop a game-theoretical approach to the solution of systems of monotone equations over lattices, where for each single equation either the least or greatest solution is taken. A simple parity game, referred to as fixpoint game, is defined that provides a correct and complete characterisation of the solution of equation systems over continuous lattices, a quite general class of lattices widely used in semantics. For powerset lattices the fixpoint game is intimately connected with classical parity games for $\mu$-calculus model-checking, whose solution can exploit as a key tool Jurdzi\'nski's small progress measures. We show how the notion of progress measure can be naturally generalised to fixpoint games over continuous lattices and we prove the existence of small progress measures. Our results lead to a constructive formulation of progress measures as (least) fixpoints. We refine this characterisation by introducing the notion of selection that allows one to constrain the plays in the parity game, enabling an effective (and possibly efficient) solution of the game, and thus of the associated verification problem. We also propose a logic for specifying the moves of the existential player that can be used to systematically derive simplified equations for efficiently computing progress measures. We discuss potential applications to the model-checking of latticed $\mu$-calculi and to the solution of fixpoint equations systems over the reals

Cellular metabolism constrains innate immune responses in early human ontogeny

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny

Global patterns of nitrate isotope composition in rivers and adjacent aquifers reveal reactive nitrogen cascading

Remediation of nitrate pollution of Earth’s rivers and aquifers is hampered by cumulative biogeochemical processes and nitrogen sources. Isotopes (δ15N, δ18O) help unravel spatiotemporal nitrogen(N)-cycling of aquatic nitrate (NO3−). We synthesized nitrate isotope data (n = ~5200) for global rivers and shallow aquifers for common patterns and processes. Rivers had lower median NO3− (0.3 ± 0.2 mg L−1, n = 2902) compared to aquifers (5.5 ± 5.1 mg L−1, n = 2291) and slightly lower δ15N values (+7.1 ± 3.8‰, n = 2902 vs +7.7 ± 4.5‰, n = 2291), but were indistinguishable in δ18O (+2.3 ± 6.2‰, n = 2790 vs +2.3 ± 5.4‰, n = 2235). The isotope composition of NO3− was correlated with water temperature revealing enhanced N-cascading in warmer climates. Seasonal analyses revealed higher δ15N and δ18O values in wintertime, suggesting waste-related N-source signals are better preserved in the cold seasons. Isotopic assays of nitrate biogeochemical transformations are key to understanding nitrate pollution and to inform beneficial agricultural and land management strategies

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Premature birth : implications for early life immunity

Premature birth is a major contributor to under-five mortality, causing approximately 1 million deaths every year. This vulnerability stems from the high susceptibility of neonates, particularly those born prematurely, to severe life-threatening infections. The overarching goal of my thesis work was to study the immunological basis for preterm neonates’ vulnerability to infections. It was previously known that monocytes isolated from preterm cord blood show suppressed responses to innate immune activation. In Chapter 2, we employed untargeted transcriptomics comparing monocytes at rest and after LPS stimulation, from neonates born preterm (37 weeks gestation) and from adults. Results establish cellular energy metabolism as a major regulator of innate immune responsiveness during fetal life, perhaps to purposely limit overt inflammation in utero. Additionally, our experiments suggested a central role for mTORC1, and its negative regulator DDIT4L in suppressing innate immune responses in preterm monocytes. In Chapter 3, I developed a monocytic cell line model to study the impact of DDIT4L on innate immune function. DDIT4L overexpression limited protein synthesis, cellular proliferation and LPS-induced cytokine production. Additionally, experiments in primary neonatal monocytes revealed developmental changes in mitochondrial function. Lastly, data linking reduced DDIT4L expression to more severe inflammatory lung disease in preterm neonates point towards a putative role in preventing inflammatory-mediated tissue damage in neonates. Beyond the immediate postnatal period, preterm infants remain particularly vulnerable to respiratory viral infections. In Chapter 4, I studied infants at high-risk for respiratory syncytial virus (RSV) infections. I showed that most infants have been exposed to RSV, as evidenced by increased IgM titers, Fc receptor binding and antibody-mediated phagocytosis by the end of their first winter season. Overall, my study suggests that most high-risk preterm infants develop antibody responses against RSV by one year of age, in the absence of overt clinical signs. This challenges the dogma that preterm infants are unable to fight respiratory illnesses without getting sick and provide insights into the highest period of vulnerability to these viruses. In sum, my work provides fundamental insights into the maturation of immune responses in the first year of life in premature babies.Medicine, Faculty ofExperimental Medicine, Division ofGraduat

MR-guided adaptive radiotherapy for bladder cancer

Radiotherapy has an important role in the curative and palliative treatment settings for bladder cancer. As a target for radiotherapy the bladder presents a number of technical challenges. These include poor tumor visualization and the variability in bladder size and position both between and during treatment delivery. Evidence favors the use of magnetic resonance imaging (MRI) as an important means of tumor visualization and local staging. The availability of hybrid systems incorporating both MRI scanning capabilities with the linear accelerator (MR-Linac) offers opportunity for in-room and real-time MRI scanning with ability of plan adaption at each fraction while the patient is on the treatment couch. This has a number of potential advantages for bladder cancer patients. In this article, we examine the technical challenges of bladder radiotherapy and explore how magnetic resonance (MR) guided radiotherapy (MRgRT) could be leveraged with the aim of improving bladder cancer patient outcomes. However, before routine clinical implementation robust evidence base to establish whether MRgRT translates into improved patient outcomes should be ascertained