Optimal infinite scheduling for multi-priced timed automata

This paper is concerned with the derivation of infinite schedules for timed automata that are in some sense optimal. To cover a wide class of optimality criteria we start out by introducing an extension of the (priced) timed automata model that includes both costs and rewards as separate modelling features. A precise definition is then given of what constitutes optimal infinite behaviours for this class of models. We subsequently show that the derivation of optimal non-terminating schedules for such double-priced timed automata is computable. This is done by a reduction of the problem to the determination of optimal mean-cycles in finite graphs with weighted edges. This reduction is obtained by introducing the so-called corner-point abstraction, a powerful abstraction technique of which we show that it preserves optimal schedules. This work has been mostly done while visiting CISS at Aalborg University in Denmark and has been supported by CISS and by ACI Cortos, a program of the French Ministry of Research.     

National and International Water Law

Abstract

The exchange of data and information relating to transboundary water resources is widely accepted as being an appropriate starting point for more comprehensive cooperation. This paper examines under what conditions data and information exchange occur in relation to shared water resources, and hence examines when it can be used as a confidence building measure. An overview of several major international river basins together with more detailed case studies of the Mekong. Rio Grande, and Rhine River basins suggest that factors that promote data and information exchange include the presence of compatible needs, absence of legacies of mistrust, increasing water resources stress, perceptions that cooperation is of mutual benefit, external pressure and funding, comparable levels of institutional capacity, popular and political concern about water resources management, and functional formal or informal cooperative arrangements. Analysis of the situation prevailing between Israel and the Palestinians with regard to shared water resources suggests that data and information exchange does not seem likely in the short term, even though other forms of cooperation have been established with mixed results. This suggests that in some situations, at least, data and information exchange relating to shared water resources may not be useful as a first step in establishing more comprehensive cooperation.     

Replacing dichromate with hydrogen peroxide in the chemical oxygen demand (COD) test

The widely used standard method for chemical oxygen demand (COD) involves hazardous chromium species, and its two-hour heating protocol entails a substantial amount of energy expenditure. In the present work we report a proof of concept for a major modification of this method in the range 10-800 mgCOD/L, whereby H2O2 is proposed as a replacement oxidizer. This modification not only reduces the use of unsafe chromium species but also allows for the use of milder conditions that decrease the total energy outlay. The results are comparable with those obtained either with the standard method or with a commercial Hach? kit.     

Inverse Analysis of Impact Test Data: Experimental Study on Polymeric Materials Displaying Brittle Behaviour

This paper deals with the influence of the testing equipment on impact load measurements. A previously developed method of analysis and processing of the experimental data based on a refined analogical model of the impact event and inverse problem techniques is used. This method makes it possible to obtain the mechanical response of the material, notwithstanding the disturbance of the dynamic effects associated to the test. Results from tests carried out both on falling weight and swing pendulum instrumented testing machines are compared. It is shown that this method can give an accurate estimation of the actual bending force in impact testing independent of the testing equipment.     

Charging effect in electron-irradiated ice

To maintain the original distribution pattern of diffusible elements in biological samples, electron probe microanalysis is carried out with frozen hydrated bulk specimens and cryosections, analysed at temperatures below 130 K. Ice has a very low intrinsic conductivity at this working temperature and surface- and space-charging appears, when uncoated specimens are irradiated with non-penetrating electrons. Although coating with a grounded conductor abolishes the surface potential, the build-up of an internal space-charge field is possible, depending on the sample thickness and beam voltage used. Consequently, the geometry of the X-ray source volume and the spectral distribution of the emitted continuous and characteristic X-rays are affected. To simulate the situation for microanalysis of frozen hydrated specimens the charging process in electron irradiated ice is studied by recording simultaneous specimen currents from the top and bottom of ice layer preparations. The external currents yield information on the build-up of internal space-charge fields which result from the balance of charge injection, storage, and transport. Irradiation of uncoated bulk specimens with a finely focused beam results in the build-up of a space-charge field close to the surface, which causes a reduction of the depth of microprobe analysis. In coated bulk specimens the induced conductivity renders possible a current flow to the front electrode, thereby limiting the space-charge field. Sections with an effective rear electrode will not charge appreciably if the electron range is larger than about half the section thickness.     

Near-Complete Remission of Glioblastoma in a Patient Treated with an Allogenic Dendritic Cell-Based Vaccine: The Role of Tumor-Specific CD4+T-Cell Cytokine Secretion Pattern in Predicting Response and Recurrence

Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic–tumor cell fusion vaccine. CST showed a near-complete tumor response, with a marked improvement in her functional status and simultaneous increases in tumor-specific CD8+ and CD4+ T cells. Two months before recurrence, the frequency of tumor-specific T cells decreased, while that of IL-17 and CD4+ T cells increased. CST passed away 15 months after enrollment. In this illustrative case, the tumor-specific CD4+ T-cell numbers and phenotype behaved as treatment efficacy biomarkers, highlighting the key role of the latter in glioblastoma immunotherapy.     

Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO₂), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn²⁺) and oxidative stress (known as the “ROS hypothesis”) have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn²⁺ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn²⁺, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn²⁺ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH.     

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)—known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis—was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion^®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.     

Enapotamab Vedotin,an AXL-Specific Antibody-Drug Conjugate,Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.