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The viscoplastic behavior of polycrystalline $\mathrm{Mg}_{2}\mathrm{SiO}_{4}$ wadsleyite aggregates, a major high pressure phase of the mantle transition zone of the Earth (depth range: 410–520 km), is obtained by properly bridging several scale transition models. At the very fine nanometric scale corresponding to the dislocation core structure, the behavior of thermally activated plastic slip is modeled for strain-rates relevant for laboratory experimental conditions, at high pressure and for a wide range of temperatures, based on the Peierls–Nabarro–Galerkin model. Corresponding single slip reference resolved shear stresses and associated constitutive equations are deduced from Orowan’s equation in order to describe the average viscoplastic behavior at the grain scale, for the easiest slip systems. These data have been implemented in two grain-polycrystal scale transition models, a mean-field one (the recent Fully-Optimized Second-Order Viscoplastic Self-Consistent scheme of [1]) allowing rapid evaluation of the effective viscosity of polycrystalline aggregates, and a full-field (FFT based [2, 3]) method allowing investigating stress and strain-rate localization in typical microstructures and heterogeneous activation of slip systems within grains. Calculations have been performed at pressure and temperatures relevant for in-situ conditions. Results are in very good agreement with available mechanical tests conducted at strain-rates typical for laboratory experiments.

This book aims to show, in a nuanced and precise way, the effects of deindustrialization on a territory of eastern France. This can change the electoral behaviour of a population whose habits have been upset by the closure of businesses and the dislocation of the community they helped to forge. Another development contributes to these changes: the aging of the population and the departure of young people, which is accelerating after the 2000s. The old world also began to disintegrate under the influence of factors such as the entry into the consumer society and the weakening of religious practices.

The proliferation of the Internet of Things (IoT) is occurring swiftly and is all-encompassing. The cyber attack on Dyn in 2016 brought to light the notable susceptibilities of intelligent networks. The issue of security in the realm of the Internet of Things (IoT) has emerged as a significant concern. The security of the Internet of Things (IoT) is compromised by the potential danger posed by exploiting devices connected to the Internet. The susceptibility of Things to botnets poses a significant threat to the entire Internet ecosystem (smart devices). In recent years, there has been a simultaneous evolution in the complexity and variety of security attack vectors. Therefore, it is imperative to analyse IoT methodologies to detect and alleviate emerging security breaches. The present study analyses network datasets, distinguishing between those of the Internet of Things (IoT) and those that do not, and provides a thorough overview of the findings. Our primary focus is on IoT Network Intrusion Detection (NID) studies, wherein we examine the available datasets, tools, and machine learning (ML) techniques employed in the implementation of network intrusion detection (NID). Subsequently, an evaluation, assessment, and summary of the current state-of-the-art research on IoT-related Network Intrusion Detection (NID) conducted between 2018 and 2024 is presented. This includes an analysis of the publication year, dataset, attack types, experiment results, and the advantages, disadvantages, and classifiers employed in the studies. This review emphasises research related to IoT NID that employs Supervised Machine Learning classifiers, owing to the high success rate of such classifiers in security and privacy domains. Furthermore, this survey incorporates a comprehensive analysis of research endeavours on IoT NID. Furthermore, we have identified publicly available IoT datasets that can be utilised for NID experiments, which would benefit academic and industrial research purposes. Moreover, we analyse potential prospects and future advancements. The review’s findings indicate that the Internet of Things (IoT) has been substantiated by its swift proliferation in recent times, leading to even broader network coverage. This study presented conventional datasets gathered over a decade ago and current datasets published within the past decade and utilised in recent research. The survey provides a succinct overview of prevailing research trends in IoT NID for security professionals.

Training and certification of personnel in capsule preparation are essential procedures, overseen by the pharmacist who delegates these tasks. These procedures aim not only to ensure the efficacy and safety of operations but also to establish a clear chain of responsibility. They align with established best practices. Certification grants formal authorization to qualified individuals to perform specific tasks. For new hires, a comprehensive training program is designed to facilitate their integration and empower them from the onset. We propose training objectives structured around a competency-based approach, highlighting objective evaluation criteria applicable in real-world practical settings. These training objectives address critical aspects such as the handling of hazardous substances, weighing and mixing of powders, and capsule filling. They also emphasize the importance of documentation and traceability. Specialized preparations and tools are offered to facilitate the assessment of learning outcomes.

Abstract Purpose Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. Material and methods [18F]FluoroEstradiol positron emission tomography (FES-PET), [18F]FluoroDeoxyGlucose (FDG) PET, and [18F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7-Y537S mutant ERα+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki-67 were assessed by immunohistochemistry (IHC). The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti-tumor activity. Results After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERα expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 (− 64%) but not different from the group dosed with palbociclib alone (− 46%). The impact on proliferation is corroborated by Ki-67 IHC data for both groups of treatment. Conclusions In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.

Novel therapies are needed for effective treatment of AML. In the relapsed setting, prognosis is very poor despite salvage treatment with chemotherapy. Evidence suggests that leukemic stem cells (LSCs) cause relapse. The cell surface receptor CD123 is highly expressed in blast cells and LSCs from AML patients and is a potential therapeutic target. CD123 cross-over dual-variable domain T-cell engager (CD123-CODV-TCE) is a bispecific antibody with an innovative format. One arm targets the CD3εδ subunit of T-cell co-receptors on the surface of T cells, while the other targets CD123 on malignant cells, leading to cell-specific cytotoxic activity. Here, we describe the preclinical activity of CD123-CODV-TCE. CD123-CODV-TCE effectively binds to human and cynomolgus monkey CD3 and CD123 and is a highly potent T-cell engager. It mediates T-cell activation and T-cell-directed killing of AML cells in vitro. In vivo, CD123-CODV-TCE suppresses AML tumor growth in leukemia xenograft mouse models, where it achieves an effective half-life of 3.2 days, which is a significantly longer half-life compared to other bispecific antibodies with no associated Fc fragment. The in vitro safety profile is as expected for compounds with similar modes of action. These results suggest that CD123-CODV-TCE may be a promising therapy for patients with relapsed/refractory AML.

New challenges and other topics in non-clinical safety testing of biotherapeutics were presented and discussed at the nineth European BioSafe Annual General Membership meeting in November 2019. The session topics were selected by European BioSafe organization committee members based on recent company achievements, agency interactions and new data obtained in the non-clinical safety testing of biotherapeutics, for which data sharing would be of interest and considered as valuable information. The presented session topics ranged from strategies of in vitro testing, immunogenicity prediction, bioimaging, and developmental and reproductive toxicology (DART) assessments to first-in-human (FIH) dose prediction and bioanalytical challenges, reflecting the entire space of different areas of expertise and different molecular modalities. During the 9th meeting of the European BioSafe members, the following topics were presented and discussed in 6 main sessions (with 3 or 4 presentations per session) and in three small group breakout sessions: 1) DART assessment with biotherapeutics: what did we learn and where to go?; 2) Non-animal testing strategies; 3) Seeing is believing: new frontiers in imaging; 4) Predicting immunogenicity during early drug development: hope or despair?; 5) Challenges in FIH dose projections; and 6) Non-canonical biologics formats: challenges in bioanalytics, PKPD and biotransformation for complex biologics formats. Small group breakout sessions were organized for team discussion about 3 specific topics: 1) Testing of cellular immune function in vitro and in vivo; 2) MABEL approach (toxicology and pharmacokinetic perspective); and 3) mRNA treatments. This workshop report presents the sessions and discussions at the meeting.

La révolution de 1917 est très fortement ressentie sur le territoire de la future Estonie. La crise multiforme enclenchée par la Première Guerre mondiale, couplée avec l’obsolescence de rapports sociaux d’un autre âge et la montée des aspirations nationales, constitue le terreau sur lequel s’aiguisent des contradictions de plus en plus violentes. Cependant, ce processus de dégradation par étapes ne doit pas être considéré comme fatal, ni même comme entièrement logique, la part des facteurs conjoncturels y étant très importante. La déclaration d’indépendance de 1918 qui vient couronner cette phase ne peut donc être pensée comme une évidence, pas plus d’ailleurs que la victoire ultime des nationalistes.

This review paper focuses on dislocations and plastic deformation in magnesium oxide crystals. MgO is an archetype ionic ceramic with refractory properties which is of interest in several fields of applications such as ceramic materials fabrication, nano-scale engineering and Earth sciences. In its bulk single crystal shape, MgO can deform up to few percent plastic strain due to dislocation plasticity processes that strongly depend on external parameters such as pressure, temperature, strain rate, or crystal size. This review describes how a combined approach of macro-mechanical tests, multi-scale modeling, nano-mechanical tests, and high pressure experiments and simulations have progressively helped to improve our understanding of MgO mechanical behavior and elementary dislocation-based processes under stress.

The civil war of 1918 was a very painful episode in Finnish history. The winners did everything to justify their actions and to criticize their opponents. Historical research has long been under the weight of this partisan memory. This article aims to identify ways to achieve a more balanced view of this tragic event by questioning its causes, the respective nature of the opposing forces, the real meaning of violence, and the traps and pitfalls of memory.

En Finlande, le parti social-démocrate est vite confronté aux obligations d’un parti de masse. Il lui faut développer des formes de propagande adéquates en direction d’un lectorat d’artisans, d’ouvriers qualifiés et de métayers. Ceux-ci sont d’autant plus réceptifs au message diffusé que le style et la structure des brochures correspondent assez bien à leur degré d’éducation et à leurs attentes culturelles.