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关键词： artificial neural network   Bayesian inference   COx claystone   Kriging-based reliability analysis   uncertainty quantification   visco-elastoplastic behavior  

摘要： The excavation-induced fractured zone (EFZ) and the anisotropic evolution in time of drifts' convergence, as observed in the Mesue/Haute-Marne Underground Researche Laboratory (MHM URL), reveal the complex behavior of Callovo-Oxfordian (COx) claystone, the host formation for geological radioactive waste disposal project (Cig & eacute;o) in France. Especially, the dispersion of the in situ convergence monitoring exhibits the non-negligible uncertainty of the host rock properties that must be quantified and considered in the stability analysis of the repositories' support systems. In this work, the well-known Bayesian inference with the transitional Markov chain Monte Carlo sampling technique is chosen to quantify the uncertainty of the short- and long-term behavior of COx claystone and EFZ using the convergence data of a drift excavated in the major horizontal stress direction. An engineering approach is adopted to simulate the anisotropy of drift convergence. To reduce the computational cost of the numerical model prediction during the probabilistic inversion, the artificial neural network-based surrogate is chosen. The uncertainty of the visco-elastoplastic behavior of COx claystone, as well as the uncertainty of the EFZ shape, is then considered in the reliability analysis of the concrete liner of an intermediate-level long-lived radioactive (IL-LLW) repository. The numerical applications allow verifying the robustness of the current design for the repository support system.

关键词： muscle atrophy   NF-kappa B   Puerarin   sarcopenia   TNF-alpha  

摘要： Sarcopenia, marked by the loss of muscle mass and function, is a chronic condition that worsens with age. Currently, there are no effective drugs for its treatment. Puerarin, a potent natural compound extracted from the root of Pueraria lobata, exhibits various pharmacological properties, including anti-inflammatory, antioxidative, and anti-apoptotic effects. It remains unclear whether puerarin possesses anti-muscle atrophy capabilities. This study aims to evaluate the effectiveness of puerarin in delaying the development of muscle atrophy in mice with dexamethasone-induced sarcopenia and to explore the underlying molecular mechanisms. Experimental findings reveal that puerarin effectively alleviates a range of physiological and behavioral changes caused by dexamethasone, including weight loss, deterioration in muscle mass and function, and destruction of the ultrastructure of muscle fibers. Notably, puerarin significantly enhances muscle mass and function in mice with dexamethasone-induced sarcopenia, reduces the release of pro-inflammatory cytokines while promoting the production of anti-inflammatory factors, lowers oxidative stress, inhibits the expression of muscle apoptosis proteins, and decelerates muscle atrophy development by suppressing the TNF-alpha/NF-kappa B signaling pathway. In conclusion, these findings not only further confirm the potential value of puerarin as a therapeutic drug for sarcopenia but also provide new directions and theoretical foundations for future research.

关键词： Pneumonia   Diabetes   Innate immunity   Streptococcus pneumoniae   Legionella pneumophila  

摘要： Diabetes mellitus is associated with an increased risk of pneumonia, often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a variety of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with S. pneumoniae or L. pneumophila, type 2 diabetic and prediabetic mice exhibited higher bacterial loads in their lungs compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised IFN gamma production by natural killer cells in diabetic and prediabetic mice, which was associated with reduced IL-12 production by CD103+ dendritic cells. Blocking IFN gamma enhanced susceptibility of non-diabetic mice to L. pneumophila, while IFN gamma treatment restored defense against this intracellular pathogen in diabetic animals. In contrast, IFN gamma treatment did not increase resistance of diabetic mice to S. pneumoniae, suggesting that impaired IFN gamma production is not the sole mechanism underlying the heightened susceptibility of these animals to pneumococcal infection. Thus, our findings uncover a mechanism that could help to explain how type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFN gamma-mediated antibacterial defense against atypical lung pathogens.

关键词： Low back pain   Intervertebral disc degeneration   PPI network   Proteomics   Candidate prioritisation   Prioritisation algorithm  

摘要： Protein-protein interaction (PPI) networks provide a static map of functional protein interactions, which when combined with algorithms, can prioritize key protein candidates which experimental studies cannot capture. This study, aimed to construct knowledge-based nucleus pulposus (NP)-specific PPI networks which could be deployed to investigate complex protein interactions in human NP cells and tissues following IL-4 and IL-10 stimulation. NP-specific PPI networks were developed based on mass spectrometry (MS) and secretome data-sets from human NP cells. These networks were validated using in vitro and ex vivo experimental data sets. Genes Underlying Inheritance Linked Disorders (GUILD) genome-wide network-based prioritization framework was employed for protein candidate prediction under no treatment baseline and IL-4, IL-10 and IL-1 beta single or combined stimulating scenarios. These secretome-based in vitro PPI networks were able to reproduce the no-treatment candidate prioritization baseline. Whereby within NP cells from discs isolated due to traumatic injury biglycan was identified whilst in degenerate samples decorin was highlighted. Furthermore, experimentally observed IL-4 pleiotropic behaviour was predicted by IL-1 receptor-like 1 prioritization. PPI network-based IL-4 and IL-10 conditions offered novel insights of potential candidates, including collagen IV and fibroblast growth factor intracellular binding protein (FIBP) as key candidates within IL-4 activation pathways, whereas urocortin 3 and neural growth factor were identified following IL-10 stimulation. Additionally, MS based PPI network propagation offered a more extensive, module-based structure networks with lower edge degree and biological variability. Overall, multiple proteomic experimental approaches are required to successfully validate in-silico prediction models to understand the complex interactions between the plethora of proteins involved in IVD degeneration.

关键词： rheumatoid arthritis   JAK inhibitor   IL-6 receptor inhibitor   treatment  

摘要： Objectives A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyse the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent *** The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with *** The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (P = 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri *** IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

关键词： Triple-negative breast cancer   Lipopolysaccharide   Toll-like receptor 4  

摘要： Triple-negative breast cancer (TNBC) is a metastatic disease. Targeted approaches, as implementing nanoliposomes, e.g., liposomal doxorubicin (DOX), did not exhibit significantly improved survival. Therefore, we aimed at reducing the metastatic potential of TNBC through a double punch to cancer cells and tumor-associated macrophages (TAMs). Databases' analyses showed that targeting TLR4/SIRT2 axis might be a possible option. Inspired by the emergence of lipopolysaccharide (LPS) in clinical trials, we developed bioactive copolymeric nanomicelles, originating from the self-assembly of our synthesized LPS-pectin conjugate (LPS-PEC) for the delivery of DOX (DOX@LPS-PEC). Targeting TLR4 via DOX@LPS-PEC micelles enhanced cellular uptake, however, it failed to significantly improve the cytotoxic potential of DOX. Alternatively, co-targeting SIRT2 via Sirtinol at a specific ratio (DOX@LPS-PEC: Sirtinol 1:5 w/w) elevated cellular oxidative stress, improved cytotoxic potential on 2D-monolayer and 3D-spheroid models, and significantly reduced migratory potential of MDAMB-231 cells compared to DOX@LPS-PEC alone. Finally, DOX@LPS-PEC plus Sirtinol at the same ratio exhibited an ability to hamper TAM-secreted IL6, which contribute to the metastatic potential of TNBC. In conclusion, targeting TLR4/SIRT2 axis in TNBC synergizes with the effect of chemotherapeutics, e.g. DOX, reduce the metastatic potential of TNBC cells via down-regulating TLR4 and hampering tumor-microenvironment IL6.

关键词： Colitis ulcerosa   entzündlichen Darmerkrankungen   CED   TNF   Antikörper   Sphingosin   1   Phosphat   Rezeptor   Interleukin   23   Januskinasen   JAK   Inhibitoren   Ulcerative colitis   inflammatory bowel diseases   IBD   TNF antibodies   Sphingosine   1   phosphate receptor   Interleukin   23   Janus kinases   JAK inhibitors  

摘要： Despite advances in drug therapy for ulcerative colitis, rates of primary and/or secondary treatment failure are still considerable. Numerous new agents have been developed and approved in recent years. In this article, we discuss case-based decision-making processes for selecting appropriate anti-inflammatory treatments in UC patients and summarize the principles of the various therapeutic strategies.

关键词： HLA-DRB1*08:03:16   next-generation sequencing   novel allele  

摘要： HLA-DRB1*08:03:16 differs from HLA-DRB1*08:03:02:01 by one nucleotide substitution at position 528 G>T.

关键词： acute kidney damage   Araliaceae   Eleutherococcus senticosus   fasudil   aristolochic acid nephropathy   inflammatory vesicles  

摘要： Eleutherococcus senticosus (ES) exerts various pharmacological effects, including renoprotection in a rat model of renal ischemia-reperfusion injury. However, the mechanisms of these effects remain unclear. Therefore, we investigated the effects and mechanisms of ES on aristolochic acid (AA)-induced acute kidney injury in mice. The experimental mice were divided into the control group, the model group (AA-induced acute kidney injury model), the model + ES group ( Eleutherococcus senticosus boiled-free granules treated by gavage for two weeks), the model + fasudil group (fasudil administered intraperitoneally for three days), and the model + ES + fasudil group. After AA intervention in normal mice, the expression of ASC and NLRP3 and the levels of IL-1 beta , IL-18, and TNF- alpha were significantly elevated in mouse renal tissues (P < 0.05). However, AA-induced renal dysfunction was ameliorated by both ES and fasudil, which was confirmed by the decrease in serum creatinine and blood urea nitrogen levels, as well as by renal histopathological abnormalities such as renal tubule dilation and tubular formation. In addition, the inflammatory response of AA-induced renal inflammation was inhibited by both ES and fasudil, and the expression of ASC and NLRP3 and the levels of IL-1 beta , IL-18, and TNF- alpha were significantly higher in mouse renal tissues after the treatment of either ES or fasudil (P < 0.05). ES may be a potential treatment agent for aristolochic-acid-triggered nephropathy, with inhibition of the NLRP3/IL-1 beta as one plausible underlying mechanism.

关键词： HLA-B   nanopore sequencing technology   next-generation sequencing   novel allele  

摘要： HLA-B*48:43:02 differs from HLA-B*48:43:01 by one single nucleotide substitution at position 900 G>C in exon 5.