Specifying time-sensitive systems with TLA+

International audienceWe present a pattern-based method to express time specifications in the language TLA+. A real-time module RealTimeNew is introduced to encapsulate the definitions of commonly used time patterns. We present a general framework to differentiate the temporal characterizations from system functionality with time constraints. The temporal specification is concise and provably as a refinement of its corresponding functional description without time. The method ameliorates the usability of TLA+ in specifying and verifying time-sensitive systems. A case study is harnessed to illustrate and validate the approach

Modeling and Analysis of Stage Machinery Control Systems by Timed Colored Petri Nets

International audienceThis paper presents an approach and successful experience of applying timed colored Petri nets on modeling and analyzing a stage machinery control system. The programmable logic controllers (PLCs) based system is modeled with timing constraints. The compositionality is incorporated in the modeling process of the entire design. The PLC synchronization problem with the interactions of environment is analyzed by the state space analysis method. The case studies demonstrate the effectiveness of the approach

Promoting Long-Term Survival of Insulin-Producing Cell Grafts That Differentiate from Adipose Tissue-Derived Stem Cells to Cure Type 1 Diabetes

BACKGROUND: Insulin-producing cell clusters (IPCCs) have recently been generated in vitro from adipose tissue-derived stem cells (ASCs) to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long-term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, β cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so. CONCLUSIONS/SIGNIFICANCE: Long-term survival of ASC-derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation

Manipulating IL-2 Availability Amid Presentation of Donor MHC Antigens Suppresses Murine Alloimmune Responses by Inducing Regulatory T Cells

BACKGROUND: Major histocompatibility complex (MHC) antigens are important for alloimmune responses as well as immune tolerance. Previous studies have shown that presentation of donor MHC antigens by donor-specific transfusion prior to or upon transplantation promotes transplant tolerance induced by other agents. However, it is unclear whether presentation of donor MHC antigens by DNA vaccination induces long-term allograft survival. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether presentation of MHC class-II and/or class-I donor antigens by DNA vaccination suppresses alloimmune responses and promotes long-term allograft acceptance. We initially found that presentation of both MHC donor antigens by DNA vaccination itself prior to transplantation fails to significantly prolong islet allograft survival in otherwise untreated mice. However, islet allograft survival was significantly prolonged when MHC class-II DNA vaccination was accompanied with IL-2 administration (MHCII + IL-2) while MHC class-I DNA vaccination was followed by IL-2 and subsequent neutralizing anti-IL-2 treatments (MHCI + IL-2/anti-IL-2). Especially, this protocol promoted long-term allograft survival in the majority of recipients (57%) when combined with low doses of rapamycin post-transplantation. Importantly, MHCII + IL-2 induced FoxP3+ Treg cells in both spleens and grafts and suppressed graft-infiltrating CD4+ cell proliferation, whereas MHCI + IL-2/anti-IL-2 mainly inhibited graft-infiltrating CD8+ cell proliferation and donor-specific CTL activity. The combined protocol plus rapamycin treatment further reduced both CD4+ and CD8+ T cell proliferation as well as donor-specific CTL activity but spared FoxP3+ Treg cells. Depleting CD25+ Treg cells or adoptive transfer of pre-sensitized CD8+ T cells abolished this long-term allograft survival. CONCLUSIONS/SIGNIFICANCE: Manipulating IL-2 availability during presentation of MHC class-II and class-I donor antigens by DNA vaccination pre-transplantation induces Treg cells, suppresses alloimmune responses and promotes long-term allograft survival

Fracture and Delamination Assessment of Prestressed Composite Concrete for Use with Pipe Jacking Method

Prestressed composite concrete pipe (PCCP) has been widely used in water-transmission line and has been proven with many advantages over pure concrete or steel pipes, such as high performance with relatively low cost for materials as well as simplified installation and construction process. Recent efforts have been made to enable the PCCP structure suitable for pipe jacking method so as to replace the conventional cut and cover method. In this way, the construction time, disturbance to nearby structures, and the cost can be greatly reduced. In this paper, we present the full-scale experimental and numerical studies of PCCP and the evaluation of fracture and delamination behaviour of the structure when it is used with pipe jacking construction method subjected to various jacking forces and ground conditions

Carbohydrate intake quality and gestational diabetes mellitus, and the modifying effect of air pollution

BackgroundNutritional management is the cornerstone of gestational diabetes mellitus (GDM) prevention. High quality instead of low quantity of carbohydrate intake has been paying attention in controlling glycemia. Air pollution exposure can be interacted with dietary sourced nutrients, which may modify the associations with GDM. This study aims to explore the associations between overall quality of carbohydrate intake and GDM as well as the modifying effect of prenatal air pollution exposure.MethodsCarbohydrate quality index (CQI) was calculated was calculated by summing scores of the four components; Land use regression prediction models were used to assess the air pollution exposure levels. GDM definition was based on 75 g glucose tolerance test results. Associations between pre-pregnancy CQI, pre-natal air pollution as well as the modifying effect on GDM were explored based on a birth cohort in China.ResultsA total of 3,183 participants were included, of which 784 (24.63%) were diagnosed with GDM. Higher pre-pregnancy CQI was associated with a lower incidence of GDM [odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.56–0.99, Pfor trend = 0.04], especially for higher fasting blood glucose related GDM (OR = 0.66, 95% CI: 0.47, 0.91). Higher air pollution exposure before and during pregnancy was associated with a greater risk of GDM. Higher exposure to particulate matter with an aerodynamic diameter of < 2.5 μm (Pfor interaction < 0.01), particulate matter with an aerodynamic diameter of < 10 μm (Pfor interaction < 0.01), and sulfur dioxide (Pfor interaction = 0.02) during pregnancy decreased the beneficial effect of high pre-pregnancy CQI on GDM.ConclusionCQI related dietary interventions pre-pregnancy to prevent GDM incidence should be considered. Women who are planning to be pregnant should avoid high exposure to air pollution during pregnancy