Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

Background/AimsHepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC.MethodsWe investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types.ResultsRegulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis.ConclusionsWe revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC

All-Electrical Skyrmionic Bits in a Chiral Magnetic Tunnel Junction

Topological spin textures such as magnetic skyrmions hold considerable promise as robust, nanometre-scale, mobile bits for sustainable computing. A longstanding roadblock to unleashing their potential is the absence of a device enabling deterministic electrical readout of individual spin textures. Here we present the wafer-scale realization of a nanoscale chiral magnetic tunnel junction (MTJ) hosting a single, ambient skyrmion. Using a suite of electrical and multi-modal imaging techniques, we show that the MTJ nucleates skyrmions of fixed polarity, whose large readout signal - 20-70% relative to uniform states - corresponds directly to skyrmion size. Further, the MTJ exploits complementary mechanisms to stabilize distinctly sized skyrmions at zero field, thereby realizing three nonvolatile electrical states. Crucially, it can write and delete skyrmions using current densities 1,000 times lower than state-of-the-art. These results provide a platform to incorporate readout and manipulation of skyrmionic bits across myriad device architectures, and a springboard to harness chiral spin textures for multi-bit memory and unconventional computing.Comment: 8 pages, 5 figure

microRNA-203 Modulates Wound Healing and Scar Formation via Suppressing Hes1 Expression in Epidermal Stem Cells

Background/Aims: Little is known how miR-203 is involved in epidermal stem cells (ESCs) differentiation and scar formation. Methods: We first used luciferase assay to determine the interaction of miR-203 with the 3’-UTR in regulation of Hes1 expression. We then used flow cytometry to analyze the effects of miR-203 expression on the differentiation of ESCs to MFB by determination of CK15 ratio and α-SMA. To confirm the results of flow cytometry analysis, we used Western blot to examine the expression of α-SMA, Collagen I (Col I), and Collagen III (Col III), as well as the expression of Notch1, Jagged1, and Hes1 in ESCs after the treatment of pre-miR-203 or anti-miR-203. Finally, we examined the effects local anti-miR-203 treatment on would closure and scar formation using a mouse skin wound model. Results: Pre-miR-203 treatment increased ESCs differentiation to MFB cells, as indicated by decreased CK15 ratio and increased MFB biomarkers. This phenomenon was reversed by overexpression of Hes1 in ESCs. In addition, skin incision increased expression of miR-203 in wound tissue. Local treatment of anti-miR-203 could accelerate wound closure and reduce scar formation in vivo, which was associated with increased re-epithelialization, skin attachment regeneration, and collagen reassignment. Finally, we confirmed that anti-miR-203 treatment could inhibit ESCs differentiation in vivo via increasing Hesl expression. Conclusion: Taken together, our results suggested that overexpression of miR-203 in ESCs after skin wound may be a critical mechanism underlying the scar formation

Edge Weld Penetration Assessment via Electric Current Deflection Measurements

Because of the awkward and somewhat irregular shape of the weldment, conventional methods [1] could not be adapted to the nondestructive measurement of GTAW edge weld penetration on clamshell-style catalytic converters and a special inspection system based on the electric current deflection method was developed. DC or low-frequency AC electric resistance measurements, also known as the Potential Drop Method (PDM), are well-developed for plate thickness assessment and crack detection [2–6]. The operating principle of these methods is that, under certain arrangement of the electrodes, the defect or crack in a conducting specimen will cause a measurable increase in resistance between given points compared to the situation without the defect or crack. In recent years, this simple contact technique was largely obscured by more sophisticated noncontacting eddy-current techniques especially in industrial applications. In this article, we demonstrate the distinct advantages of the Potential Drop Method through the example of GTAW edge welds where the awkward shape of the specimens and the required large penetration depth render the eddy-current method less feasible.</p

A Collaborative Despeckling Method for SAR Images Based on Texture Classification

Speckle is an unavoidable noise-like phenomenon in Synthetic Aperture Radar (SAR) imaging. In order to remove speckle, many despeckling methods have been proposed during the past three decades, including spatial-based methods, transform domain-based methods, and non-local filtering methods. However, SAR images usually contain many different types of regions, including homogeneous and heterogeneous regions. Some filters could despeckle effectively in homogeneous regions but could not preserve structures in heterogeneous regions. Some filters preserve structures well but do not suppress speckle effectively. Following this theory, we design a combination of two state-of-the-art despeckling tools that can overcome their respective shortcomings. In order to select the best filter output for each area in the image, the clustering and Gray Level Co-Occurrence Matrices (GLCM) are used for image classification and weighting, respectively. Clustering and GLCM use the co-registered optical images of SAR images because their structure information is consistent, and the optical images are much cleaner than SAR images. The experimental results on synthetic and real-world SAR images show that our proposed method can provide a better objective performance index under a strong noise level. Subjective visual inspection demonstrates that the proposed method has great potential in preserving structural details and suppressing speckle noise

Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis

Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown-like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARγ expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII-AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFα, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders.Ministry of Health (MOH)National Medical Research Council (NMRC)Published versionThis work was supported by the Singapore National Research Foundation under its CBRG grant (NMRC/CBRG/0070/2014) and administrated by the Singapore Ministry of Health’s National Medical Research Council