Comprehensibility of UML-based Formal Model – A Series of Controlled Experiments

This paper summarises two controlled experiments conducted on a model that integrates the use of semi-formal notation, the Unified Modelling Language (UML) and a formal notation, B. The experiments assessed the comprehensibility of the model, namely UML-B. The first experiment compared the comprehensibility of a UML-B model and a B model. In the second experiment, the model was compared with an Event-B model, a new generation of B. The experiments assessed the ability of the model to present information and to promote problem domain understanding. The measurement focused on the efficiency in performing the comprehension tasks. The experiments employed a cross-over design and were conducted on third-year and masters students. The results suggest that the integration of semi-formal and formal notations expedites the subjects’ comprehension tasks with accuracy even with limited hours of training

Refining Nodes and Edges of State Machines

State machines are hierarchical automata that are widely used to structure complex behavioural specifications. We develop two notions of refinement of state machines, node refinement and edge refinement. We compare the two notions by means of examples and argue that, by adopting simple conventions, they can be combined into one method of refinement. In the combined method, node refinement can be used to develop architectural aspects of a model and edge refinement to develop algorithmic aspects. The two notions of refinement are grounded in previous work. Event-B is used as the foundation for our refinement theory and UML-B state machine refinement influences the style of node refinement. Hence we propose a method with direct proof of state machine refinement avoiding the detour via Event-B that is needed by UML-B

Sexual selection and assortative mating : an experimental test

This work was funded by the Marie Curie Initial Training Network ‘Understanding the evolutionary origin of biological diversity’ (ITN-2008-213780 SPECIATION) and by a US National Science Foundation grant (DEB 0093149) and NERC grants (NE/B504065/1; NE/D003741/1) to RRS.Mate choice and mate competition can both influence the evolution of sexual isolation between populations. Assortative mating may arise if traits and preferences diverge in step, and, alternatively, mate competition may counteract mating preferences and decrease assortative mating. Here, we examine potential assortative mating between populations of Drosophila pseudoobscura that have experimentally evolved under either increased (‘polyandry’) or decreased (‘monogamy’) sexual selection intensity for 100 generations. These populations have evolved differences in numerous traits, including a male signal and female preference traits. We use a two males: one female design, allowing both mate choice and competition to influence mating outcomes, to test for assortative mating between our populations. Mating latency shows subtle effects of male and female interactions, with females from the monogamous populations appearing reluctant to mate with males from the polyandrous populations. However, males from the polyandrous populations have a significantly higher probability of mating regardless of the female's population. Our results suggest that if populations differ in the intensity of sexual selection, effects on mate competition may overcome mate choice.PostprintPeer reviewe

Fatty-acid uptake in prostate cancer cells using dynamic microfluidic raman technology

It is known that intake of dietary fatty acid (FA) is strongly correlated with prostate cancer progression but is highly dependent on the type of FAs. High levels of palmitic acid (PA) or arachidonic acid (AA) can stimulate the progression of cancer. In this study, a unique experimental set-up consisting of a Raman microscope, coupled with a commercial shear-flow microfluidic system is used to monitor fatty acid uptake by prostate cancer (PC-3) cells in real-time at the single cell level. Uptake of deuterated PA, deuterated AA, and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were monitored using this new system, while complementary flow cytometry experiments using Nile red staining, were also conducted for the validation of the cellular lipid uptake. Using this novel experimental system, we show that DHA and EPA have inhibitory effects on the uptake of PA and AA by PC-3 cells

Advances in Chimeric Antigen Receptor T-Cell Therapies for Solid Tumors.

In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed living drugs for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being used to implement CAR T-cell immunotherapy for the treatment of solid tumors

Towards a method for rigorous development of generic requirements patterns

We present work in progress on a method for the engineering, validation and verification of generic requirements using domain engineering and formal methods. The need to develop a generic requirement set for subsequent system instantiation is complicated by the addition of the high levels of verification demanded by safety-critical domains such as avionics. Our chosen application domain is the failure detection and management function for engine control systems: here generic requirements drive a software product line of target systems. A pilot formal specification and design exercise is undertaken on a small (twosensor) system element. This exercise has a number of aims: to support the domain analysis, to gain a view of appropriate design abstractions, for a B novice to gain experience in the B method and tools, and to evaluate the usability and utility of that method.We also present a prototype method for the production and verification of a generic requirement set in our UML-based formal notation, UML-B, and tooling developed in support. The formal verification both of the structural generic requirement set, and of a particular application, is achieved via translation to the formal specification language, B, using our U2B and ProB tools

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

Nonequilibrium Temperature and Thermometry in Heat-Conducting Phi-4 Models

We analyze temperature and thermometry for simple nonequilibrium heat-conducting models. We show in detail, for both two- and three-dimensional systems, that the ideal gas thermometer corresponds to the concept of a local instantaneous mechanical kinetic temperature. For the Phi-4 models investigated here the mechanical temperature closely approximates the local thermodynamic equilibrium temperature. There is a significant difference between kinetic temperature and the nonlocal configurational temperature. Neither obeys the predictions of extended irreversible thermodynamics. Overall, we find that kinetic temperature, as modeled and imposed by the Nos\'e-Hoover thermostats developed in 1984, provides the simplest means for simulating, analyzing, and understanding nonequilibrium heat flows.Comment: 20 pages with six figures, revised following review at Physical Review

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer

New Langevin and Gradient Thermostats for Rigid Body Dynamics

We introduce two new thermostats, one of Langevin type and one of gradient (Brownian) type, for rigid body dynamics. We formulate rotation using the quaternion representation of angular coordinates; both thermostats preserve the unit length of quaternions. The Langevin thermostat also ensures that the conjugate angular momenta stay within the tangent space of the quaternion coordinates, as required by the Hamiltonian dynamics of rigid bodies. We have constructed three geometric numerical integrators for the Langevin thermostat and one for the gradient thermostat. The numerical integrators reflect key properties of the thermostats themselves. Namely, they all preserve the unit length of quaternions, automatically, without the need of a projection onto the unit sphere. The Langevin integrators also ensure that the angular momenta remain within the tangent space of the quaternion coordinates. The Langevin integrators are quasi-symplectic and of weak order two. The numerical method for the gradient thermostat is of weak order one. Its construction exploits ideas of Lie-group type integrators for differential equations on manifolds. We numerically compare the discretization errors of the Langevin integrators, as well as the efficiency of the gradient integrator compared to the Langevin ones when used in the simulation of rigid TIP4P water model with smoothly truncated electrostatic interactions. We observe that the gradient integrator is computationally less efficient than the Langevin integrators. We also compare the relative accuracy of the Langevin integrators in evaluating various static quantities and give recommendations as to the choice of an appropriate integrator.Comment: 16 pages, 4 figure