Event structures for Petri nets with persistence

Event structures are a well-accepted model of concurrency. In a seminal paper by Nielsen, Plotkin and Winskel, they are used to establish a bridge between the theory of domains and the approach to concurrency proposed by Petri. A basic role is played by an unfolding construction that maps (safe) Petri nets into a subclass of event structures, called prime event structures, where each event has a uniquely determined set of causes. Prime event structures, in turn, can be identified with their domain of configurations. At a categorical level, this is nicely formalised by Winskel as a chain of coreflections. Contrary to prime event structures, general event structures allow for the presence of disjunctive causes, i.e., events can be enabled by distinct minimal sets of events. In this paper, we extend the connection between Petri nets and event structures in order to include disjunctive causes. In particular, we show that, at the level of nets, disjunctive causes are well accounted for by persistent places. These are places where tokens, once generated, can be used several times without being consumed and where multiple tokens are interpreted collectively, i.e., their histories are inessential. Generalising the work on ordinary nets, Petri nets with persistence are related to a new subclass of general event structures, called locally connected, by means of a chain of coreflections relying on an unfolding construction

Bisimilarity and Behaviour-Preserving Reconfigurations of Open Petri Nets

We propose a framework for the specification of behaviour-preserving reconfigurations of systems modelled as Petri nets. The framework is based on open nets, a mild generalisation of ordinary Place/Transition nets suited to model open systems which might interact with the surrounding environment and endowed with a colimit-based composition operation. We show that natural notions of bisimilarity over open nets are congruences with respect to the composition operation. The considered behavioural equivalences differ for the choice of the observations, which can be single firings or parallel steps. Additionally, we consider weak forms of such equivalences, arising in the presence of unobservable actions. We also provide an up-to technique for facilitating bisimilarity proofs. The theory is used to identify suitable classes of reconfiguration rules (in the double-pushout approach to rewriting) whose application preserves the observational semantics of the net.Comment: To appear in "Logical Methods in Computer Science", 41 page

Iron in Porphyrias: Friend or Foe?

Iron is a trace element that is important for many vital processes, including oxygen transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when defective at the level of one of the eight enzymes involved, can cause the development of a group of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease development/progression or as a potential therapeutic target or molecule, is still being debated, since contrasting results have emerged from clinical observations, in vitro studies and animal models. In this review we aim to deepen such aspects by drawing attention to the current evidence on the role of iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and effective management

verifying a behavioural logic for graph transformation systems

We propose a framework for the verication of behavioural properties of systems modelled as graph transformation systems. The properties can be expressed in a temporal logic which is basically a -calculus where the state predicates are formulae of a monadic second order logic, describing graph properties. The verication technique relies on an algorithm for the construction of nite over-approximations of the unfolding of a graph transformation system

Critical concepts, practice recommendations, and research perspectives of pixantrone therapy in non-Hodgkin lymphoma: a SIE, SIES, and GITMO consensus paper

Objectives: In this paper, we present a review of critical concepts and research perspectives and produce recommendations on the optimal use of pixantrone in non-Hodgkin lymphoma (NHL) by group discussion from an expert panel appointed by the Italian Society of Hematology and the affiliate societies, Societa Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo. Methods: Recommendations were produced using the Delphi process. Scientific evidence on pixantrone efficacy was analyzed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology in the areas where at least one randomized trial was published. The following key issues were addressed for practical recommendations: pixantrone monotherapy in aggressive relapsed or refractory non-Hodgkin B-cell lymphomas and toxicity risk management in patients candidates to pixantrone. Results and conclusions: After a balanced and value-oriented discussion, the panel agreed that the benefit/risk profile was in favor of pixantrone in the treatment of adult patients with multiply relapsed or refractory aggressive NHL B-cell lymphomas. Pixantrone was deemed to be contraindicated in patients with uncontrolled cardiovascular disease. Despite a low rate of cardiotoxicity of pixantrone reported in clinical trials, the panel recommended that all patients receiving pixantrone should undergo periodical cardiac monitoring

Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

Abstract Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin low/neg HLA-DR − CD11b + CD33 + CD14 + ) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively ( P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate ( P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD

Specific issues concerning the management of patients on the waiting list and after liver transplantation

The present document is a second contribution collecting the recommendations of an expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF) concerning the management of certain aspects of liver transplantation, including: the issue of prompt referral; the management of difficult candidates; malnutrition; living related liver transplants; hepatocellular carcinoma; and the role of direct acting antiviral agents before and after transplantation. The statements on each topic were approved by participants at the AISF Transplant Hepatology Expert Meeting organized by the Permanent Liver Transplant Commission in Mondello on 12-13 May 2017. They are graded according to the GRADE grading system

Serum and Liver Iron Differently Regulate the Bone Morphogenetic Protein 6 (BMP6)-SMAD Signaling Pathway in Mice

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo