The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction

Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenance of life and that characterize the execution of activities of daily life generally present periodic variations, which are mostly synchronized with the light-dark cycle determined by Earth's rotation on its axis. These rhythms with 24-h periodicity, defined as circadian, influence events linked to the interaction between hosts and hosted microorganisms and can dramatically determine the outcome of this interplay. As for the various pathological conditions resulting from host-microorganism interactions, a particularly interesting scenario concerns infections by viruses. When a viral agent enters the body, it alters the biological processes of the infected cells in order to favour its replication and to spread to various tissues. Though our knowledge concerning the mutual influence between the biological clock and viruses is still limited, recent studies start to unravel interesting aspects of the clock-virus molecular interplay. Three different aspects of this interplay are addressed in this mini-review and include the circadian regulation of both innate and adaptive immune systems, the impact of the biological clock on viral infection itself, and finally the putative perturbations that the virus may confer to the clock leading to its deregulation

A sound algorithm for asynchronous session subtyping and its implementation

Session types, types for structuring communication between endpoints in concurrent systems, are recently being integrated into mainstream programming languages. In practice, a very important notion for dealing with such types is that of subtyping, since it allows for typing larger classes of systems, where a program has not precisely the expected behavior but a similar one. Unfortunately, recent work has shown that subtyping for session types in an asynchronous setting is undecidable. To cope with this negative result, the only approaches we are aware of either restrict the syntax of session types or limit communication (by considering forms of bounded asynchrony). Both approaches are too restrictive in practice, hence we proceed differently by presenting an algorithm for checking subtyping which is sound, but not complete (in some cases it terminates without returning a decisive verdict). The algorithm is based on a tree representation of the coinductive definition of asynchronous subtyping; this tree could be infinite, and the algorithm checks for the presence of finite witnesses of infinite successful subtrees. Furthermore, we provide a tool that implements our algorithm. We use this tool to test our algorithm on many examples that cannot be managed with the previous approaches, and to provide an empirical evaluation of the time and space cost of the algorithm

A Multi-Layered Study on Harmonic Oscillations in Mammalian Genomics and Proteomics

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components

Undecidability of asynchronous session subtyping

Session types are used to describe communication protocols in distributed systems and, as usual in type theories, session subtyping characterizes substitutability of the communicating processes. We investigate the (un)decidability of subtyping for session types in asynchronously communicating systems. We first devise a core undecidable subtyping relation that is obtained by imposing limitations on the structure of types. Then, as a consequence of this initial undecidability result, we show that (differently from what stated or conjectured in the literature) the three notions of asynchronous subtyping defined so far for session types are all undecidable. Namely, we consider the asynchronous session subtyping by Mostrous and Yoshida for binary sessions, the relation by Chen et al. for binary sessions under the assumption that every message emitted is eventually consumed, and the one by Mostrous et al. for multiparty session types. Finally, by showing that two fragments of the core subtyping relation are decidable, we evince that further restrictions on the structure of types make our core subtyping relation decidable.Comment: 36 page

The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes

Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics

A Sound Algorithm for Asynchronous Session Subtyping and its Implementation

Session types, types for structuring communication between endpoints in distributed systems, are recently being integrated into mainstream programming languages. In practice, a very important notion for dealing with such types is that of subtyping, since it allows for typing larger classes of system, where a program has not precisely the expected behaviour but a similar one. Unfortunately, recent work has shown that subtyping for session types in an asynchronous setting is undecidable. To cope with this negative result, the only approaches we are aware of either restrict the syntax of session types or limit communication (by considering forms of bounded asynchrony). Both approaches are too restrictive in practice, hence we proceed differently by presenting an algorithm for checking subtyping which is sound, but not complete (in some cases it terminates without returning a decisive verdict). The algorithm is based on a tree representation of the coinductive definition of asynchronous subtyping; this tree could be infinite, and the algorithm checks for the presence of finite witnesses of infinite successful subtrees. Furthermore, we provide a tool that implements our algorithm. We use this tool to test our algorithm on many examples that cannot be managed with the previous approaches, and to provide an empirical evaluation of the time and space cost of the algorithm

A Sound Algorithm for Asynchronous Session Subtyping

Session types, types for structuring communication between endpoints in distributed systems, are recently being integrated into mainstream programming languages. In practice, a very important notion for dealing with such types is that of subtyping, since it allows for typing larger classes of system, where a program has not precisely the expected behavior but a similar one. Unfortunately, recent work has shown that subtyping for session types in an asynchronous setting is undecidable. To cope with this negative result, the only approaches we are aware of either restrict the syntax of session types or limit communication (by considering forms of bounded asynchrony). Both approaches are too restrictive in practice, hence we proceed differently by presenting an algorithm for checking subtyping which is sound, but not complete (in some cases it terminates without returning a decisive verdict). The algorithm is based on a tree representation of the coinductive definition of asynchronous subtyping; this tree could be infinite, and the algorithm checks for the presence of finite witnesses of infinite successful subtrees. Furthermore, we provide a tool that implements our algorithm and we apply it to many examples that cannot be managed with the previous approaches

On the boundary between decidability and undecidability of asynchronous session subtyping

Session types are behavioural types for guaranteeing that concurrent programs are free from basic communication errors. Recent work has shown that asynchronous session subtyping is undecidable. However, since session types have become popular in mainstream programming languages in which asynchronous communication is the norm rather than the exception, it is crucial to detect significant decidable subtyping relations. Previous work considered extremely restrictive fragments in which limitations were imposed to the size of communication buffer (at most 1) or to the possibility to express multiple choices (disallowing them completely in one of the compared types). In this work, for the first time, we show decidability of a fragment that does not impose any limitation on communication buffers and allows both the compared types to include multiple choices for either input or output, thus yielding a fragment which is more significant from an applicability viewpoint. In general, we study the boundary between decidability and undecidability by considering several fragments of subtyping. Notably, we show that subtyping remains undecidable even if restricted to not using output covariance and input contravariance

Foundations of Session Types and Behavioural Contracts

International audienceBehavioural type systems, usually associated to concurrent or distributed computations, encompass concepts such as interfaces, communication protocols, and contracts, in addition to the traditional input/output operations. The behavioural type of a software component specifies its expected patterns of interaction using expressive type languages, so that types can be used to determine automatically whether the component interacts correctly with other components. Two related important notions of behavioural types are those of session types and behavioural contracts. This paper surveys the main accomplishments of the last twenty years within these two approaches