On the Expressiveness of Pure Safe Ambients

We consider the Pure Safe Ambient Calculus, which is Levi and Sangiorgi's Safe Ambient Calculus (a variant of Cardelli and Gordon's Mobile Ambient Calculus) restricted to its mobility primitives, and we focus on its expressiv- e power. Since it has no form of communication or substitution, we show how these notions can be simulated by mobility and modifications in the hierarchical structure of ambients. As a main result, we use these techniques to design an encoding of the synchronous pi-calculus into pure ambients, and we study its correctness, thus showing that pure ambients are as expressive as the pi-calculus. In order to simplify the proof and give an intuitive understanding of the encoding, we design an intermediate language: the pi-calculus with Explicit Substitutions and Channels, which is an extension of the pi-calculus in which communication and substitution are broken into simpler steps, and we show that is has the same expressive power as the pi-calculus

A Calculus for Context-Awareness

In order to answer the challenge of pervasive computing, we propose a new process calculus, whose aim is to describe dynamic systems composed of agents able to move and react differently depending on their location. This Context-Aware Calculus features a hierarchical structure similar to mobile ambients, and a generic multi-agent synchronization mechanism, inspired from the join-calculus. After general ideas and introduction, we review the full calculus' syntax and semantics, as well as some motivating examples, study its expressiveness, and show how the notion of computation itself can be made context-dependent

Using Ambients to Control Resources (long version)

Current software and hardware systems, being parallel and reconfigurable, raise new safety and reliability problems, and the resolution of these problems requires new methods. Numerous proposals attempt at reducing the threat of bugs and preventing several kinds of attacks. In this paper, we develop an extension of the calculus of Mobile Ambients, named Controlled Ambients, that is suited for expressing such issues, specifically Denial of Service attacks. We present a type system for Controlled Ambients, which makes static resource control possible in our setting

Optimisation multicritère de composants mécaniques à l’aide d’une approche par satisfaction de contraintes

Nous proposons d’examiner les apports des techniques de programmation par contrainte en conception et notamment en optimisation de composants mécaniques. Nous présentons le cadre théorique de modélisation d’un problème de satisfaction de contraintes, les principes de résolution et de recherche d’optimum ainsi que leur utilisation potentielle en ingénierie de produit. Un exemple concret d’application au dimensionnement optimal d’une transmission de puissance par adhérence est finalement traité

study protocol for a randomized controlled trial

Background Osteoarthritis (OA) is a heterogeneous group of conditions with disturbed integrity of articular cartilage and changes in the underlying bone. The pathogenesis of OA is multifactorial and not just a disease of older people. Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) typically used for the treatment of various rheumatic and dermatologic diseases. Three studies of HCQ in OA, including one abstract and one letter, are available and use a wide variety of outcome measures in small patient populations. Despite initial evidence for good efficacy of HCQ, there has been no randomized, double-blind, and placebo-controlled trial in a larger patient group. In the European League Against Rheumatism (EULAR), evidence-based recommendations for the management of hand OA, HCQ was not included as a therapeutic option because of the current lack of randomized clinical trials. Methods/Design OA TREAT is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial. A total of 510 subjects with inflammatory and erosive hand OA, according to the classification criteria of the American College of Rheumatology (ACR), with recent X-ray will be recruited across outpatient sites, hospitals and universities in Germany. Patients are randomized 1:1 to active treatment (HCQ 200 to 400 mg per day) or placebo for 52 weeks. Both groups receive standard therapy (non-steroidal anti-inflammatory drugs [NSAID], coxibs) for OA treatment, taken steadily two weeks before enrollment and continued further afterwards. If disease activity increases, the dose of NSAID/coxibs can be increased according to the drug recommendation. The co-primary clinical endpoints are the changes in Australian-Canadian OA Index (AUSCAN, German version) dimensions for pain and hand disability at week 52. The co-primary radiographic endpoint is the radiographic progression from baseline to week 52. A multiple endpoint test and analysis of covariance will be used to compare changes between groups. All analyses will be conducted on an intention-to-treat basis. Discussion The OA TREAT trial will examine the clinical and radiological efficacy and safety of HCQ as a treatment option for inflammatory and erosive OA over 12 months. OA TREAT focuses on erosive hand OA in contrast to other current studies on symptomatic hand OA, for example, HERO [Trials 14:64, 2013]

Sustained Increase of 25-Hydroxyvitamin D Levels in Healthy Young Women during Wintertime after Three Suberythemal UV Irradiations—The MUVY Pilot Study

Objectives Vitamin D (VitD) deficiency is a health problem prevalent not only in the elderly but also in young adults. The primary objective of our observational pilot study “MUVY” (Mood, UVR, Vitamin D in Young women) was to test both the short-term and long-term effects of a series of three suberythemal UV radiation (UVR) exposures on the VitD status and well-being of young healthy women during winter in a repeat measure design. Methods 20 healthy young women (Fitzpatrick skin types I–III, aged 21–25 years) received three full body broad band UVR exposures with an escalating erythemally weighted dose schedule during one week in winter, and completed self-report questionnaires monitoring symptoms of depression (Beck Depression Inventory, BDI) and affective state/well-being (Profile of Mood States, POMS) at baseline and three days after the last UVR exposure. 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in serum at baseline, and at study days 8, 36 and 50. Results Mean baseline 25(OH)D level was 54.3 nmol/L (standard deviation (s.d.) = 24.1), with seven women having VitD deficient status. Relevant symptoms of depression, as indicated by low BDI total scores (0–8), were absent. After the three UVR exposures the increment of 25(OH)D was an average of 13.9 nmol/L (95% confidence interval (CI) = 9.4–18.4) and 26.2 pmol/L (95%CI = 7.2–45.1) for 1,25(OH)2D. Δ25(OH)D, and corresponding baseline levels were significantly and inversely associated (rho = -0.493, p = 0.027). Only 25(OH)D remained significantly increased above baseline for at least six weeks after the last UVR exposure. A strong inverse correlation of the POMS subscale “Vigor/Activity” and the increment in 1,25(OH)2D was found (rho = -0.739, p<0.001) at day 8. Conclusions Three suberythemal whole body UVR exposures during one week are a simple and suitable method for improving 25(OH)D levels during winter, for at least six weeks, and especially in young women with VitD deficient status. Trial Registration German Clinical Trials Register (Deutsches Register Kinischer Studien) DRKS0000927

Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance

The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1,000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants

Natural Killer Lysis Receptor (NKLR)/NKLR-Ligand Matching as a Novel Approach for Enhancing Anti-Tumor Activity of Allogeneic NK Cells

NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands.We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies.NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities