Biomarkers of Dementia with Lewy Bodies: Differential Diagnostic with Alzheimer’s Disease

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. Only one third of patients are correctly diagnosed due to the clinical similarity mainly with Alzheimer’s disease (AD). In this review, we evaluate the interest of different biomarkers: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage (i.e., MCI). MIBG SPECT with decreased cardiac sympathetic activity, perfusion SPECT with occipital hypoperfusion, FDG PET with occipital hypometabolism and cingulate island signs are of interest at the dementia stage but with a lower validity. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routines is not demonstrated. Concerning CSF biomarkers, many studies have already examined the relevance of AD biomarkers but also alpha-synuclein assays in DLB, so we will focus as comprehensively as possible on other biomarkers (especially those that do not appear to be directly related to synucleinopathy) that may be of interest in the differential diagnosis between AD and DLB. Furthermore, we would like to highlight the growing interest in CSF synuclein RT-QuIC, which seems to be an excellent discrimination tool but its application in clinical routine remains to be demonstrated, given the non-automation of the process.     

Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung

Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell–platelet interactions via platelet–CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.     

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.     

A survey on hygienic practices and their impact on the microbiological quality and safety in the Rwandan milk and dairy chain

This study assessed the status of hygienic practices in the Rwandan milk and dairy chain. Data collection was based on interviews with the help of a survey and site visits to farms, collection centres, milk processing companies, small‐scale cheese plants, wholesale points, supermarkets and milk shops. The observed status of good practices was further linked to actual microbiological data. It was concluded that there is a major gap in compliance with hygienic practices leading to higher levels of contaminated dairy products.     

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors.     

WorkSim: A Calibrated Agent-Based Model of the Labor Market Accounting for Workers’ Stocks and Gross Flows

This paper presents an agent-based model of the labor market. It simulates the market in the recent period at the aggregate level and at the level of the principal categories of labor, on the basis of the decisions of heterogeneous agents, firms and individuals, who interact. These decisions rely on individual computations of profits and utilities, although rationality is bounded in such a complex environment. The theoretical structure that underlies the decisions is the search concept. We apply this framework to the case of France in 2011. The model is at a scale of 1/4700. It is fairly detailed on the institutions of the labor market that constrain the agents’ decisions. Finally it is calibrated by a powerful algorithm to reproduce a large number of variables of interest. The calibrated model presents a consistent accounting system of the gross flows of the individuals between the main states, employment, distinguishing open ended contracts and fixed duration contracts, unemployment and inactivity. The simulation of the gross flows accounts enables us to analyze the patterns of mobility in a way that the observed statistics on gross flows, which are partial, cannot do. The model then characterizes the nature of the labor market under study, reproducing the high proportion of the fixed duration contracts in the hiring flows, and it points to a dualism of the French labor market.     

High‐Temperature Creep Behavior of SiOC Glass‐Ceramics: Influence of Network Carbon Versus Segregated Carbon

Three silicon oxycarbide samples with different carbon contents are analyzed in the present study with respect to their high‐temperature creep behavior. The tests were performed in compression at 1100°C, 1200°C, and 1300°C; in this temperature range the mechanism of creep relies on viscoelastic flow within the samples and has been modeled with the Jeffreys viscoelastic model. After the release of the applied mechanical stress, a viscoelastic recovery behavior was observed in all samples. The creep behavior of the investigated samples indicates two rheological contributions in SiOC: (i) a high viscous answer, coming from the silica‐rich network, and (ii) an elastic response from the segregated carbon phase within the samples. Furthermore, two distinct effects of the carbon phase on the HT creep behavior of SiOC were identified and are discussed in the present paper: the effect of the carbon presence within the SiOC network (the “carbidic” carbon), which induces a significant increase in the viscosity and a strong decrease in the activation energy for creep, as compared to vitreous silica; and the influence of the segregated carbon phase (the “free” carbon), which has been shown to affect the viscosity and the activation energy of creep and dominates the creep behavior in phase‐separated silicon oxycarbides.     

The impact of strain-induced crystallization on strain during mechanical cycling of cross-linked natural rubber

The improvement of X-ray diffraction techniques since the last ten years allowed a renewal of the study of strain-induced crystallization in natural rubber. In particular real-time measurements are now commonplace. However, due to experimental difficulties, the exploitation of the X-ray data as far as the strain state of the remaining molten fraction is concerned has been left aside. Indeed the knowledge of the local extension of the molten chains is crucial for understanding the peculiar stress behavior observed during the crystallization process. This paper presents a systematic study of this parameter during mechanical cycling performed at various temperatures. It is shown that crystallization limits the amplitude of strain endured by the molten fraction during traction. This process of strain regulation may be one explanation for the protective effect of crystallization against tearing. A precise evaluation of the contribution of the molten fraction to the retraction force during mechanical cycling is made. The role of crystallites as nanofillers may be quantified this way.