Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer

Predictors of mortality in patients with Eisenmenger syndrome and admission to the lung transplantation waiting list

Background. Patients with Eisenmenger Syndrome (ES) have very severe irreversible pulmonary hypertension but the criteria for admitting such patients to a lung transplantation waiting list (LTWL) is not clear. Indeed it has been demonstrated that the natural survival of patients with ES is better than the survival achieved through lung transplantation: it follows that no guidelines are available for these patients' admission to an LTWL. The aim of our study was to identify possible predictors of mortality in ES patients in order to reserve admission to the LTWL solely for those patients who would otherwise have the lowest probability of survival. Methods. Since 1991, 57 patients with ES from our rehabilitative centre were admitted to the LTWL of the Division of Cardiac Surgery at San Matteo Hospital, University of Pavia. At the time of the retrospective analysis, patients were divided into a group of non-transplanted survivors (27 patients - 47% of the total) and a group who had died prior to transplantation (16 patients - 28% of the total). The 14 transplanted patients (25% of the total) were not considered in the statistical analysis, considering transplantation as an "external event". Unpaired t tests were used to compare the following factors in the survivors and in those who died: sex, "complexity" of the congenital heart disease underlying the ES, previous cardiac surgery, arterial blood gases, pulmonary function and hemodynamic parameters. Moreover, a stepwise discriminant analysis was performed in order to define a possible set of prognostic factors. Results. PaCO2 was higher in those who subsequently died (36.15±7.42 mmHg) compared with those who survived (32.5±5.33 mmHg), although this difference did not reach a statistical significance (p=0.08). Discriminant analysis defined a model in which a) complexity of the congenital heart disease, b) sex (male) and c) cardiac output were predictive of a higher risk of mortality. Conclusions. This new knowledge can be used in the decision of admission to LTWL in ES patients

Non-collaborative Attackers and How and Where to Defend Flawed Security Protocols (Extended Version)

Security protocols are often found to be flawed after their deployment. We present an approach that aims at the neutralization or mitigation of the attacks to flawed protocols: it avoids the complete dismissal of the interested protocol and allows honest agents to continue to use it until a corrected version is released. Our approach is based on the knowledge of the network topology, which we model as a graph, and on the consequent possibility of creating an interference to an ongoing attack of a Dolev-Yao attacker, by means of non-collaboration actuated by ad-hoc benign attackers that play the role of network guardians. Such guardians, positioned in strategical points of the network, have the task of monitoring the messages in transit and discovering at runtime, through particular types of inference, whether an attack is ongoing, interrupting the run of the protocol in the positive case. We study not only how but also where we can attempt to defend flawed security protocols: we investigate the different network topologies that make security protocol defense feasible and illustrate our approach by means of concrete examples.Comment: 29 page

From Display to Labelled Proofs for Tense Logics

We introduce an effective translation from proofs in the display calculus to proofs in the labelled calculus in the context of tense logics. We identify the labelled calculus proofs in the image of this translation as those built from labelled sequents whose underlying directed graph possesses certain properties. For the basic normal tense logic Kt, the image is shown to be the set of all proofs in the labelled calculus G3Kt

Automating Agential Reasoning: Proof-Calculi and Syntactic Decidability for STIT Logics

This work provides proof-search algorithms and automated counter-model extraction for a class of STIT logics. With this, we answer an open problem concerning syntactic decision procedures and cut-free calculi for STIT logics. A new class of cut-free complete labelled sequent calculi G3LdmL^m_n, for multi-agent STIT with at most n-many choices, is introduced. We refine the calculi G3LdmL^m_n through the use of propagation rules and demonstrate the admissibility of their structural rules, resulting in auxiliary calculi Ldm^m_nL. In the single-agent case, we show that the refined calculi Ldm^m_nL derive theorems within a restricted class of (forestlike) sequents, allowing us to provide proof-search algorithms that decide single-agent STIT logics. We prove that the proof-search algorithms are correct and terminate

On Deriving Nested Calculi for Intuitionistic Logics from Semantic Systems

This paper shows how to derive nested calculi from labelled calculi for propositional intuitionistic logic and first-order intuitionistic logic with constant domains, thus connecting the general results for labelled calculi with the more refined formalism of nested sequents. The extraction of nested calculi from labelled calculi obtains via considerations pertaining to the elimination of structural rules in labelled derivations. Each aspect of the extraction process is motivated and detailed, showing that each nested calculus inherits favorable proof-theoretic properties from its associated labelled calculus

Chest pain and a left parasternal soft tissue swelling in an immunocompetent refugee with disseminated tuberculosis

An immunocompetent migrant with chest pain was admitted to an Italian hospital. CT scan showed a left pectoral abscess and osteomyelitis of the sternum. The infection spread into the anterior mediastinum near to the pericardium and the heart, where an atrial mass was confirmed by echocardiography. Disseminated tuberculosis was diagnosed

Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation

Sporadic cases account for 90-95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of 'idiopathic' parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell

Formal Verification of Security Protocol Implementations: A Survey

Automated formal verification of security protocols has been mostly focused on analyzing high-level abstract models which, however, are significantly different from real protocol implementations written in programming languages. Recently, some researchers have started investigating techniques that bring automated formal proofs closer to real implementations. This paper surveys these attempts, focusing on approaches that target the application code that implements protocol logic, rather than the libraries that implement cryptography. According to these approaches, libraries are assumed to correctly implement some models. The aim is to derive formal proofs that, under this assumption, give assurance about the application code that implements the protocol logic. The two main approaches of model extraction and code generation are presented, along with the main techniques adopted for each approac