Plasma exosomes from children with juvenile dermatomyositis are taken up by human aortic endothelial cells and are associated with altered gene expression in those cells

BACKGROUND: The pathology of juvenile dermatomyositis (JDM) is characterized by prominent vessel wall and perivascular inflammation. This feature of the disease has remained unexplained and under-investigated. We have hypothesized that plasma exosomes, which play an important role in inter-cellular communication, may play a role in the vascular injury associated with JDM. OBJECTIVE: To characterize the circulating exosomes of children with JDM and determine whether the small RNA cargoes within those exosomes are capable of altering transcriptional programs within endothelial cells. DESIGN/METHODS: We purified exosomes from plasma samples of children with active, untreated JDM (n = 6) and healthy controls (n = 9). We characterized the small RNA cargoes in JDM and control exosomes by RNA sequencing using the Illumina HiSeq 2500 platform. We then incubated isolated exosomes from healthy controls and children with JDM with cultured human aortic endothelial cells (HAEC) for 24 h. Fluorescence microscopy was used to confirm that both control and JDM exosomes were taken up by HAEC. RNA was then purified from HAEC that had been incubated with either control or JDM exosomes and sequenced on the Illumina platform. Differential expression of mRNAs from HAEC incubated with control or JDM exosomes was ascertained using standard computational methods. Finally, we assessed the degree to which differential gene expression in HAEC could be attributed to the different small RNA cargoes in JDM vs control exosomes using conventional and novel analytic methods. RESULTS: We identified 10 small RNA molecules that showed differential abundance when we compared JDM and healthy control exosomes. Fluorescence microscopy of labeled exosomes confirmed that both JDM and control exosomes were taken up by HAEC. Differential gene expression analysis revealed 59 genes that showed differential expression between HAEC incubated with JDM exosomes vs HAEC incubated with exosomes from controls. Statistical analysis of gene expression data demonstrated that multiple miRNAs exerted transcriptional control on multiple genes with HAEC. CONCLUSIONS: Plasma exosomes from children with active, untreated JDM are taken up by HAEC and are associated with alterations in gene expression in those cells. These findings provide new insight into potential mechanisms leading to the targeting of vascular tissue by the immune system in JDM

Lenvatinib Combined with the PD-1 Inhibitor Camrelizumab in the Treatment of Primary Liver Cancer Caused Hemorrhagic Exfoliative Gastritis

Introduction: Patients with advanced primary liver cancer often lose the opportunity for surgery when they are found, and the treatment options are limited. Lenvatinib, as a multi-target tyrosine kinase inhibitor, has been used as the first-line treatment for advanced liver cancer. Immune checkpoint inhibitors, such as programmed cell death protein 1 inhibitors, have been successfully used in advanced or metastatic liver cancer. Case Presentation: We report a case of combined lenvatinib and the programmed cell death protein 1 inhibitor camrelizumab in the treatment of primary liver cancer, in which the rare complication of full-thickness gastric mucosa exfoliation occurred. To the best of our knowledge, this is the first report of the side effect of hemorrhagic exfoliative gastritis with the combination of lenvatinib and camrelizumab. Conclusion: Hemorrhagic exfoliative gastritis is an extremely rare clinical complication. Lenvatinib inhibits vascular proliferation and could cause gastrointestinal perforation, which is considered to be the main factor, but whether camrelizumab plays a role in it or only causes gastrointestinal reactions leading to nausea and vomiting, resulting in gastric mucosal exfoliation bleeding, remains to be further explored

Generative Retrieval with Semantic Tree-Structured Item Identifiers via Contrastive Learning

The retrieval phase is a vital component in recommendation systems, requiring the model to be effective and efficient. Recently, generative retrieval has become an emerging paradigm for document retrieval, showing notable performance. These methods enjoy merits like being end-to-end differentiable, suggesting their viability in recommendation. However, these methods fall short in efficiency and effectiveness for large-scale recommendations. To obtain efficiency and effectiveness, this paper introduces a generative retrieval framework, namely SEATER, which learns SEmAntic Tree-structured item identifiERs via contrastive learning. Specifically, we employ an encoder-decoder model to extract user interests from historical behaviors and retrieve candidates via tree-structured item identifiers. SEATER devises a balanced k-ary tree structure of item identifiers, allocating semantic space to each token individually. This strategy maintains semantic consistency within the same level, while distinct levels correlate to varying semantic granularities. This structure also maintains consistent and fast inference speed for all items. Considering the tree structure, SEATER learns identifier tokens' semantics, hierarchical relationships, and inter-token dependencies. To achieve this, we incorporate two contrastive learning tasks with the generation task to optimize both the model and identifiers. The infoNCE loss aligns the token embeddings based on their hierarchical positions. The triplet loss ranks similar identifiers in desired orders. In this way, SEATER achieves both efficiency and effectiveness. Extensive experiments on three public datasets and an industrial dataset have demonstrated that SEATER outperforms state-of-the-art models significantly.Comment: 8 main pages, 3 pages for appendi

Structural Insights into Recognition of MDC1 by TopBP1 in DNA Replication Checkpoint Control

SummaryActivation of the DNA replication checkpoint by the ATR kinase requires protein interactions mediated by the ATR-activating protein, TopBP1. Accumulation of TopBP1 at stalled replication forks requires the interaction of TopBP1 BRCT5 with the phosphorylated SDT repeats of the adaptor protein MDC1. Here, we present the X-ray crystal structures of the tandem BRCT4/5 domains of TopBP1 free and in complex with a MDC1 consensus pSDpT phosphopeptide. TopBP1 BRCT4/5 adopts a variant BRCT-BRCT packing interface and recognizes its target peptide in a manner distinct from that observed in previous tandem BRCT- peptide structures. The phosphate-binding pocket and positively charged residues in a variant loop in BRCT5 present an extended binding surface for the negatively charged MDC1 phosphopeptide. Mutations in this surface reduce binding affinity and recruitment of TopBP1 to γH2AX foci in cells. These studies reveal a different mode of phosphopeptide binding by BRCT domains in the DNA damage response

Outsourced carbon mitigation efforts of Chinese cities from 2012 to 2017

Outsourced carbon mitigation between cities means that some cities benefit from the carbon mitigation efforts of other cities more than their own. This problem conceals the recognition of cities’ mitigation contributions. Here we quantify local and outsourced carbon mitigation levels from 2012 to 2017 and identified ‘outsourced mitigation beneficiaries’ relying on outsourced efforts more than their own among 309 Chinese cities by using a city-level input–output model. It found that the share of outsourced emissions rose from 78.6% to 81.9% during this period. In particular, 240 cities (77.7%) were outsourced mitigation beneficiaries, of which 65 were strong beneficiaries (their local carbon emissions still grew) and 175 cities were weak beneficiaries (with larger outsourced mitigation efforts than local mitigation efforts). Strong beneficiaries were often industrializing cities with more agriculture and light manufacturing, focusing on local economic growth. In contrast, weak beneficiaries were mainly at the downstream of supply chains with services and high-tech manufacturing, which have stronger connections with upstream heavy industry cities. The findings suggest the need for policies to manage outsourced mitigation of supply chains and encourage transformation, improving the fair acknowledgment of cities’ carbon mitigation efforts

Outsourced carbon mitigation efforts of Chinese cities from 2012 to 2017

Outsourced carbon mitigation between cities means that some cities benefit from the carbon mitigation efforts of other cities more than their own. This problem conceals the recognition of cities’ mitigation contributions. Here we quantify local and outsourced carbon mitigation levels from 2012 to 2017 and identified ‘outsourced mitigation beneficiaries’ relying on outsourced efforts more than their own among 309 Chinese cities by using a city-level input–output model. It found that the share of outsourced emissions rose from 78.6% to 81.9% during this period. In particular, 240 cities (77.7%) were outsourced mitigation beneficiaries, of which 65 were strong beneficiaries (their local carbon emissions still grew) and 175 cities were weak beneficiaries (with larger outsourced mitigation efforts than local mitigation efforts). Strong beneficiaries were often industrializing cities with more agriculture and light manufacturing, focusing on local economic growth. In contrast, weak beneficiaries were mainly at the downstream of supply chains with services and high-tech manufacturing, which have stronger connections with upstream heavy industry cities. The findings suggest the need for policies to manage outsourced mitigation of supply chains and encourage transformation, improving the fair acknowledgment of cities’ carbon mitigation efforts

Palaeoenvironment of mid- to late Holocene loess deposit of the southern margin of the Tarim Basin, NW China

Holocene environmental history in the Tarim Basin and the Taklimakan Desert is known mainly froth isolated eolian and lacustrine deposits and remain puzzling. Here we present an adequately preserved loess section, covering the past 5000 years, at a highland (2,850 m a.s.l) on the northern slope of Kunlun Mountains. Pollen preserved in the section reveal a drying trend with significant moisture fluctuations around 3000-2600 cal yr BP and 1800 cal yr BP at the study site. Comparing the pollen, grain size from the same section provides a different scene occurred in the Tarim basin and the Taklimakan desert. Comparison of grain size to A/C ration of pollen suggests that active sand southward shifting in south margin of the desert is coincident with increasing moisture condition at the section locality, implying a casual link. This moisture pattern occurred at the upper and lower elevation of the slope is best explained by the vertical variation of local precipitation along the slope

Analysis of Genomic and Immune Intratumor Heterogeneity in Linitis Plastica via Multiregional Exome and T-Cell Receptor Sequencing

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma