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Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients. Primary biliary cholangitis is a chronic autoimmune disease critically linked to immunological dysregulation but the local immune-pathogenesis is poorly understood. Here the authors present single cell transcriptomic characterisation of primary biliary cholangitis and implicates Th1 like cells in a murine model.

Many works on topological insulators have focused on periodic lattice systems; where short- and long-range order is considered. Here we construct a two-dimensional amorphous photonic crystal with short-range order and a controllable level of long-range order and experimentally investigate the transport of topological edge states in this amorphous system. We demonstrate that topology properties remain constant with unidirectional edge state propagation; immune to specific disorder strength. The partition phenomena of edge states are also observed at the intersection of four topological channels in microwave experiments. This proposed amorphous configuration provides new opportunities to explore the relationship between short-range order and topology and may alleviate the fabrication difficulties of topological optical devices for practical applications.

Background Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoiesis and in regulation of stem cells, but its physiological roles in adult HSCs are unknown. Methods We performed gene expression analysis of Dlk1, and constructed conditional Dlk1 knockout (KO) mice by crossing Mx1 cre mice with Dlk flox/flox mice. Western blot and quantitative PCR were used to detect Dlk1 KO efficiency. Flow cytometry was performed to investigate the effects of Dlk1 KO on HSCs, progenitors and linage cells in primary mice. Competitive HSCs transplantation and secondary transplantation was used to examine the effects of Dlk1 KO on long-term hematopoietic repopulation potential of HSCs. RNA-Seq and cell metabolism assays was used to determine the underlying mechanisms. Results Dlk1 was highly expressed in adult mice long-term HSCs (LT-HSCs) relative to progenitors and mature lineage cells. Dlk1 KO in adult mice HSCs drove HSCs enter active cell cycle, and expanded phenotypical LT-HSCs, but undermined its long-term hematopoietic repopulation potential. Dlk1 KO resulted in an increase in HSCs’ metabolic activity, including glucose uptake, ribosomal translation, mitochondrial metabolism and ROS production, which impaired HSCs function. Further, Dlk1 KO in adult mice HSCs attenuated Notch signaling, and re-activation of Notch signaling under Dlk1 KO decreased the mitochondrial activity and ROS production, and rescued the changes in frequency and absolute number of HSCs. Scavenging ROS by antioxidant N-acetylcysteine could inhibit mitochondrial metabolic activity, and rescue the changes in HSCs caused by Dlk1 KO. Conclusion Our study showed that Dlk1 played an essential role in maintaining HSC homeostasis, which is realized by governing cell cycle and restricting mitochondrial metabolic activity.

Although an integral part of art historical studies, authentic experiences of architecture have been excluded from the cathedrals of cultural objects, art museums. The built forms can seldomly fit into the doors of museums like art objects in a collection, due to their physical sizes and inseparable links with their surrounding environment. When architecture is presented under traditional museum setting, the visitor experience is often mediated and created by photos, videos, and scaled models. When architectures are converted into public spaces like tourists’ sites, onsite experiences in these spaces are typically biased for a particular duration of time and weather. Interaction with the space is limited due to preservation concerns. This project aims to provide an alternative architectural experience in response to these above limitations using digital methods, instead of trying to substitute the traditional museum experience or the authentic onsite experience. The digital component of this project curates a virtual space using the early access version of Unreal Engine 5, as an exploration of the state-of-the-art technologies in rendering virtual spaces. The project contains three example scenes: Church of the Light, Glass House, and Dom-Ino House. Instead of merely promoting a virtual or a physical experience of architecture, this study takes a critical stance towards the growing attention around digitization and discusses the possibilities of experiencing architecture in a virtual setting.

With the rapid development of natural language processing technology, large language models have demonstrated exceptional performance in various application scenarios. However, training these models requires significant computational resources and data processing capabilities. Cross-cloud federated training offers a new approach to addressing the resource bottlenecks of a single cloud platform, allowing the computational resources of multiple clouds to collaboratively complete the training tasks of large models. This study analyzes the key technologies of cross-cloud federated training, including data partitioning and distribution, communication optimization, model aggregation algorithms, and the compatibility of heterogeneous cloud platforms. Additionally, the study examines data security and privacy protection strategies in cross-cloud training, particularly the application of data encryption and differential privacy techniques. Through experimental validation, the proposed technical framework demonstrates enhanced training efficiency, ensured data security, and reduced training costs, highlighting the broad application prospects of cross-cloud federated training.

With the rapid development of natural language processing technology, large language models have demonstrated exceptional performance in various application scenarios. However, training these models requires significant computational resources and data processing capabilities. Cross-cloud federated training offers a new approach to addressing the resource bottlenecks of a single cloud platform, allowing the computational resources of multiple clouds to collaboratively complete the training tasks of large models. This study analyzes the key technologies of cross-cloud federated training, including data partitioning and distribution, communication optimization, model aggregation algorithms, and the compatibility of heterogeneous cloud platforms. Additionally, the study examines data security and privacy protection strategies in cross-cloud training, particularly the application of data encryption and differential privacy techniques. Through experimental validation, the proposed technical framework demonstrates enhanced training efficiency, ensured data security, and reduced training costs, highlighting the broad application prospects of cross-cloud federated training.

Copyright ©2015 Zhejiang University Press, Published by Elsevier Inc.Household Service Robotics is a collection of the latest technological advances in household service robotics in five main areas: robot systems, manipulation, navigation, object recognition, and human-robot interaction.

RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1 K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1 K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling. RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNFα but sensitizes cell death to TLRs signals.

The mucosal system serves as the primary barrier against respiratory diseases and plays a crucial role in combating viral infections through mucosal immunity. The resident microbial community constitutes the main component of the mucosal system and exerts a significant inhibitory impact on the invasion of exogenous agents. However, the precise relationship between resident microbiota, mucosal immunity, and viral infections remains incomplete. This review aims to summarize the regulatory interactions between the resident microbiota of the mucosal system and innate immune components such as mucosal immunity and trained immunity. By clarifying these complex relationships, this review seeks to identify potential targets for augmenting respiratory disease prevention strategies and developing novel vaccine formulations. Furthermore, we propose the possibility of integrating the fields of microbiome-based therapeutics and vaccine development to create multifunctional vaccine formulations capable of targeting mucosal immunity induction. Such an approach holds great potential in offering novel pathways and strategies for the prevention and treatment of respiratory diseases.

The molecular mechanisms of osteoarthritis, the most common chronic disease, remain unexplained. This study aimed to use bioinformatic methods to identify the key biomarkers and immune infiltration in osteoarthritis. Gene expression profiles (GSE55235, GSE55457, GSE77298, and GSE82107) were selected from the Gene Expression Omnibus database. A protein-protein interaction network was created, and functional enrichment analysis and genomic enrichment analysis were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) databases. Immune cell infiltration between osteoarthritic tissues and control tissues was analyzed using the CIBERSORT method. Identify immune patterns using the ConsensusClusterPlus package in R software using a consistent clustering approach. Molecular biological investigations were performed to discover the important genes in cartilage cells. A total of 105 differentially expressed genes were identified. Differentially expressed genes were enriched in immunological response, chemokine-mediated signaling pathway, and inflammatory response revealed by the analysis of GO and KEGG databases. Two distinct immune patterns (ClusterA and ClusterB) were identified using the ConsensusClusterPlus. Cluster A patients had significantly lower resting dendritic cells, M2 macrophages, resting mast cells, activated natural killer cells and regulatory T cells than Cluster B patients. The expression levels of TCA1, TLR7, MMP9, CXCL10, CXCL13, HLA-DRA, and ADIPOQSPP1 were significantly higher in the IL-1β-induced group than in the osteoarthritis group in an  in vitro qPCR experiment. Explaining the differences in immune infiltration between osteoarthritic tissues and normal tissues will contribute to the understanding of the development of osteoarthritis.