Search

Psoriasis is a chronic inflammatory skin disease that often recurs at the same locations, indicating potential epigenetic changes in lesional skin cells. In this study, we discovered that fibroblasts isolated from psoriatic skin lesions retain an abnormal phenotype even after several passages in culture. Transcriptomic profiling revealed the upregulation of several genes, including the extra domain A splice variant of fibronectin and ITGA4 in psoriatic fibroblasts. A phenotypic library screening of small-molecule epigenetic modifier drugs revealed that selective CBP/p300 inhibitors were able to rescue the psoriatic fibroblast phenotype, reducing the expression levels of extra domain A splice variant of fibronectin and ITGA4. In the imiquimod-induced mouse model of psoriasis-like skin inflammation, systemic treatment with A485, a potent CBP/p300 blocker, significantly reduced skin inflammation, immune cell recruitment, and inflammatory cytokine production. Our findings indicate that epigenetic reprogramming might represent a new approach for the treatment and/or prevention of relapses of psoriasis., Journal of Investigative Dermatology, 143 (3)

Reactive oxygen species (ROS) are critical for many cellular functions, and dysregulation of ROS involves the development of multiple types of tumors, including pancreatic cancer. However, ROS have been grouped into a single biochemical entity for a long time, and the specific roles of certain types of ROS in tumor cells (e.g., pancreatic ductal adenocarcinoma (PDAC)) have not been systematically investigated. In this work, a highly sensitive and accurate mass spectrometry-based method was applied to study PDAC cells of humans and of genetically modified animals. The results show that the oncogenic KRAS mutation promotes the accumulation of hydrogen peroxide (H2O2) rather than superoxide or hydroxyl radicals in pancreatic cancer cells. We further identified that the enriched H2O2 modifies cellular metabolites and promotes the survival of pancreatic cancer cells. These findings highlight the specific roles of H2O2 in pancreatic cancer development, which may provide new directions for pancreatic cancer therapy., Angewandte Chemie. International Edition, 62 (19), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

The early life period is considered an essential period for gut microbial colonization. Manipulating gut microbiota interventions during early life periods has been proven to be a promising method to boost healthy growth. Therefore, the aim of the present study was to investigate the effects of dietary fucoidan (Fuc) on the growth, digestive tract maturation, and gut microbiota of large yellow croaker (Larimichthys crocea) larvae. Four diets were formulated with different levels of Fuc (0.00%, 0.50%, 1.00%, and 2.00%). Results showed that dietary Fuc significantly improved the growth performance of larvae. Meanwhile, dietary Fuc promoted digestive tract maturation. Dietary 1.00% Fuc significantly improved intestinal morphology. Dietary Fuc upregulated the expression of intestinal cell proliferation and differentiation related-genes and intestinal barrier related-genes. Dietary 2.00% Fuc significantly increased the activities of brush border membranes enzymes and lipase while inhibiting α-amylase. Furthermore, dietary Fuc maintained healthy intestinal micro-ecology. In detail, dietary 1.00% and 2.00% Fuc altered the overall structure of the gut microbiota and increased the relative abundance of Bacteroidetes while decreasing the relative abundance of opportunistic pathogens and facultative anaerobe. In conclusion, appropriate dietary Fuc (1.00–2.00%) could improve the growth of large yellow croaker larvae by promoting digestive tract maturation and maintaining an ideal intestinal micro-ecology.

Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact with various immune cells and regulate immune responses have been identified. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize LECs from LNs draining B16F10 melanomas compared to non-tumor-draining LNs. Several upregulated genes with immune-regulatory potential, especially in LECs lining the subcapsular sinus floor (fLECs), were identified and validated. Interestingly, some of these genes, namely, podoplanin, CD200, and BST2, affected the adhesion of macrophages to LN LECs in vitro. Congruently, lymphatic-specific podoplanin deletion led to a decrease in medullary sinus macrophages in tumor-draining LNs in vivo. In summary, our data show that tumor-derived factors induce transcriptional changes in LECs of the draining LNs, especially the fLECs, and that these changes may affect tumor immunity. We also identified a new function of podoplanin, which is expressed on all LECs, in mediating macrophage adhesion to LECs and their correct localization in LN sinuses.

Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact with various immune cells and regulate immune responses have been identified. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize LECs from LNs draining B16F10 melanomas compared to non-tumor-draining LNs. Several upregulated genes with immune-regulatory potential, especially in LECs lining the subcapsular sinus floor (fLECs), were identified and validated. Interestingly, some of these genes, namely, podoplanin, CD200, and BST2, affected the adhesion of macrophages to LN LECs in vitro. Congruently, lymphatic-specific podoplanin deletion led to a decrease in medullary sinus macrophages in tumor-draining LNs in vivo. In summary, our data show that tumor-derived factors induce transcriptional changes in LECs of the draining LNs, especially the fLECs, and that these changes may affect tumor immunity. We also identified a new function of podoplanin, which is expressed on all LECs, in mediating macrophage adhesion to LECs and their correct localization in LN sinuses.

Multi-beam box girder bridges have been applied widely throughout the world for many years. However, the cracking of longitudinal joints between the box girders always leads to reflective cracking of the bridge decks during the service period and thus finally affects the safety and durability of the actual bridges. An embedded steel plate (ESP) strengthening method was presented by introducing carbon-A/-B glue to reinforce the longitudinal joints of old multi-beam box girder bridges for this problem. In order to evaluate the feasibility of the proposed method for actual bridges, an old multi-beam box girder bridge was reinforced, and structural parameters including strain, frequency, and deflection were obtained by adopting field tests before and after strengthening. In addition, the corresponding finite element (FE) model of the background bridge was also set up using ANASYS 18.0 to analyze the strengthening process. Analysis results of the actual bridge and FE model indicate that structural stiffness and load lateral transferring performance between the box girders were enhanced after ESP strengthening. Therefore, this proposed strengthening method can be used to improve the mechanical performance of multi-beam box girder bridges and provide reference for such bridge reinforcement.

Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity. Electronic supplementary material The online version of this article (10.1007/s10456-020-09743-9) contains supplementary material, which is available to authorized users.

With the strategic transformation of our country’s navy, the defense capability of long distance needs to be improved, which has higher requirements on the reliability and life of gas turbines. Bearing system is one of the factors that restricts the life and reliability of gas turbines. The fundamental reason is that the rolling bearings used have limited life and low reliability. Since sliding bearings have higher reliability, longer service life and lower maintenance costs, in order to improve the operation stability of a certain type of gas turbine which works under complex conditions, the former supporting elements were replaced with the more reliable tilting-pad sliding bearings. Its structure is designed according to the original structural dimensions. After finishing the structure design, we analyze the static characteristics of the designed bearing from the aspects like oil film pressure, oil film thickness, bearing capacity and so on, combining with the relevant Matlab program and provide a reference for the subsequent theoretical analysis after completing the subsequent bearing on-machine test.

This study considers the problem of adaptive detection for a multichannel signal in the presence of spatially and temporally correlated compound-Gaussian disturbance. By modelling the disturbance as a multichannel autoregressive process, the authors resort to a parametric generalised likelihood ratio test (PGLRT) with the capability of dimension reduction. In the derivation, due to treating the random texture components of disturbance as deterministic unknown parameters, the test requires no a priori knowledge about the disturbance statistics. Moreover, the involving highly non-linear maximum-likelihood (ML) estimation procedure underlying the PGLRT is subtly addressed by ad hoc ML estimators. Accordingly, the derived detector applies to challenging cases with limited or even no training signals for parameter estimation. Such cases (especially when training-free case) are attractive for signal detection in heterogeneous or fast changing environments. In simulations, the performance evaluations are conducted by means of Monte Carlo trials. Numerical results investigate the issues of the estimator efficiency, detection and false alarm probabilities in terms of several concerned cases. Compared to the existing and benchmark detectors, the proposed PGLRT achieves improved detection performance, in general.

Key points Contractility of lymphatic collectors is essential for the functionality of the lymphatic system and, thus, for lymph flow. Previously published rates of lymphatic collectors in mice vary from 1.1 to 17 contractions/min with little agreement between investigators. In this study, we focused on the effects of different anaesthesia regimens on lymphatic vessel contractility using in vivo imaging approaches. We show that isoflurane and pentobarbital have an inhibitory effect on lymphatic contractility compared to mice under other anaesthesia regimens and in awake conditions. These results should help to establish a standardization of lymphatic contraction studies in mice and may also have relevance for patients undergoing anaesthesia during surgery. Abstract Contractions of collecting lymphatic vessels are essential for the function of the lymphatic vascular system, due to the lack of a central pump to drive flow. A wide range of physiological contraction frequencies and strengths have been reported in previous in vivo studies in mice. This is probably due to the different types of anaesthesia that have been used and which might have exerted direct influences on lymphatic vessel function. We investigated six commonly used anaesthesia regimens for their influence on lymphatic vessel contractility using near-infrared in vivo imaging approaches. Non-invasive imaging of the lymphatic leg collector revealed distinct effects of the anaesthesia regimens with reduced contraction activity under isoflurane and pentobarbital anaesthesia. Isoflurane also reduced the contractility of near-infrared dye-loaded vessels during invasive imaging of the lymphatic flank collector whereas the combination of ketamine/xylazine/acepromazine had no major effects. The transport time of a lymphatic-specific dye from the skin through the lymphatic vasculature to the systemic bloodstream was also delayed under isoflurane anaesthesia. Based on these results, we recommend use of combinations of ketamine and medetomidine for future non-invasive studies and of ketamine, xylazine and acepromazine for invasive studies. Beyond their importance for facilitating the interpretation and planning of animal studies, our findings might also have relevance for human patients undergoing anaesthesia for surgical procedures.

At present, one of the bottlenecks that currently restrict the reliability and lifetime of the whole machine is the rotor-bearing system of gas turbines. This paper firstly introduces the background of gas turbines and the current research situation, and then carries out 3D modelling using UG (Unigraphics NX) software according to the available 2D drawings of the original rotor and relevant parameters. In view of the complex structure of the original rotor and the technical problems in the actual installation process, the original bearing-rotor system was modified and modelled in 3D as well, followed by modal analysis and Campbell diagrams based on Ansys Workbench software. Finally, the simulation results were compared with the theoretical results to verify the feasibility of the scheme and to provide theoretical support for the subsequent 1:1 gas turbine rotor-bearing performance test-bed for the comprehensive performance experimental study of the research and development of gas turbine bearings.

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood. Methods The Ptf1aCre/+ LSL-KrasG12D/+ and Ptf1aCre/+ LSL-KrasG12D/+ LSL-p53R172H/+ and cerulein-induced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM. Results We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic KrasG12D-induced transformation. Genetic ablation of mir-802 cooperates with KrasG12D by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802–RhoA–F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival. Conclusions We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802–RhoA–F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.

Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169+ macrophages as the predominant macrophage subtype in naive LNs, which undergo proliferative expansion in response to tumor stimuli. CD169+ LN macrophage depletion, using an anti-CSF-1R antibody or clodronate-loaded liposomes, leads to increased metastatic burden in two mouse breast cancer models. The expansion of CD169+ macrophages is tightly connected to B cell expansion in tumor-draining LNs, and B cell depletion abrogates the effect of CD169+ macrophage absence on metastasis, indicating that the CD169+ macrophage anti-metastatic effects require B cell presence. These results reveal a protective role of CD169+ LN macrophages in breast cancer metastasis and raise caution for the use of drugs aiming at the depletion of tumor-associated macrophages, which might simultaneously deplete macrophages in tumor-draining LNs., Cell Reports, 35 (2), ISSN:2666-3864, ISSN:2211-1247

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC- and LEC-specific lncRNAs identified LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LETR1 acts as a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.

Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169

Lymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases, including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus (SCS) have an unanticipated function in scavenging of modified low-density lipoprotein (LDL) and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new, to our knowledge, insights into the diversity of LECs in murine LNs and a rich resource for future studies into the regulation of immune responses by LN LECs., PLoS Biology, 18 (4), ISSN:1544-9173, ISSN:1545-7885