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

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

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

Metal-to-insulator transition in oxide semimetals by anion doping

Oxide semimetals exhibiting both nontrivial topological characteristics stand as exemplary parent compounds and multiple degrees of freedom, offering great promise for the realization of novel electronic states. In this study, we present compelling evidence of profound structural and transport phase shifts in a recently uncovered oxide semimetal, SrNbO3, achieved through effective in-situ anion doping. Notably, a remarkable increase in resistivity of more than three orders of magnitude at room temperature is observed upon nitrogen-doping. The extent of electronic modulation in SrNbO3 is strongly correlated with the misfit strain, underscoring its phase instability to both chemical doping and crystallographic symmetry variations. Using first-principles calculations, we discern that elevating the level of nitrogen doping induces an upward shift in the conductive bands of SrNbO3-dNd. Consequently, a transition from a metallic state to an insulating state becomes apparent as the nitrogen concentration reaches a threshold of 1/3. This investigation sheds light on the potential of anion engineering in oxide semimetals, offering pathways for manipulating their physical properties. These insights hold promise for future applications that harness these materials for tailored functionalities.Comment: 18 pages, 4 figure

MDC1 collaborates with TopBP1 in DNA replication checkpoint control

The DNA damage checkpoint protein MDC1 also interacts with TopBP1 to promote DNA replication checkpoint control

Energy-Economical Heuristically Based Control of Compass Gait Walking on Stochastically Varying Terrain

Investigation uses simulation to explore the inherent tradeoffs ofcontrolling high-speed and highly robust walking robots while minimizing energy consumption. Using a novel controller which optimizes robustness, energy economy, and speed of a simulated robot on rough terrain, the user can adjust their priorities between these three outcome measures and systematically generate a performance curveassessing the tradeoffs associated with these metrics