Myeloid Trem2 ameliorates the progression of metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. METHODS: Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. RESULTS: Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFß1, thereby promoting tissue repair. CONCLUSIONS: Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD.

Site-Specific Anchoring a Luminescent Tag in a Protein with Non-Emissive Iridium(III) Complex.

Site-specific modification of proteins with synthetic fluorescent tag effectively improves the resolution of imaging, and such a labeling method with negligible three-dimensional structural perturbations and minimal impact on the biological functions of proteins is of high interest to dissect the high-resolution activities of biomolecules in complex systems. To this end, several non-emissive iridium(III) complexes [Ir(C-N)2 (H2 O)2 ]+ OTF- (C-N denotes various cyclometalated ligands) were designed and synthesized. These complexes were tested for attaching a protein by coordinating to H/X (HisMet, HisHis, and HisCys) that are separated by i and i+4 in α-helix. Replacement of the two labile water ligands in the iridium(III) complex by a protein HisHis pair increases the luminescent intensity up to over 100 folds. This labeling approach has been demonstrated in a highly specific and efficient manner in a number of proteins, and it is also feasible for labeling target proteins in cell lysates.

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3.

BACKGROUND: Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis. METHODS: Colorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. RESULTS: Hepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR. CONCLUSIONS: Our study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.

Pilot Feasibility Study of a Multi-View Vision Based Scoring Method for Cervical Dystonia.

Abnormal movement of the head and neck is a typical symptom of Cervical Dystonia (CD). Accurate scoring on the severity scale is of great significance for treatment planning. The traditional scoring method is to use a protractor or contact sensors to calculate the angle of the movement, but this method is time-consuming, and it will interfere with the movement of the patient. In the recent outbreak of the coronavirus disease, the need for remote diagnosis and treatment of CD has become extremely urgent for clinical practice. To solve these problems, we propose a multi-view vision based CD severity scale scoring method, which detects the keypoint positions of the patient from the frontal and lateral images, and finally scores the severity scale by calculating head and neck motion angles. We compared the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) subscale scores calculated by our vision based method with the scores calculated by a neurologist trained in dyskinesia. An analysis of the correlation coefficient was then conducted. Intra-class correlation (ICC)(3,1) was used to measure absolute accuracy. Our multi-view vision based CD severity scale scoring method demonstrated sufficient validity and reliability. This low-cost and contactless method provides a new potential tool for remote diagnosis and treatment of CD.

Ghrelin/GHS-R1a signaling plays different roles in anxiety-related behaviors after acute and chronic caloric restriction.

The brain-gut hormone ghrelin and its receptor GHS-R1a, the growth hormone secretagogue receptor 1a, regulates diverse functions of central nervous system including stress response and mood. Both acute and chronic caloric restrictions (CR) were reported to increase endogenous ghrelin level meanwhile regulate anxiety-related behaviors; however, the causal relationship between CR-induced ghrelin elevation and anxiety are not fully established. Here, we introduced an acute (24 h) and a chronic (10wks) CR procedure to both GHS-R1a KO (Ghsr-/-) mice and WT (Ghsr+/+) littermates, and compared their anxiety-related behaviors. We found that acute CR induced anxiolytic and anti-despairing behaviors in Ghsr+/+ mice but not in Ghsr-/- mice. Ad-libitum refeeding abolished the effect of acute CR on anxiety-related behaviors. In contrast, chronic CR for 10wks facilitated despair-like behavior meanwhile inhibited anxiety-like behavior in Ghsr+/+ mice. GHS-R1a deficiency rescued despair-like behavior while did not affect anxiolytic response induced by chronic CR. In addition, we found elevated interleukin-6 (IL-6) in serum of Ghsr+/+ mice after chronic CR, but not in Ghsr-/- mice. Altogether, our findings indicated that acute CR and chronic CR have different impacts on anxiety-related behaviors, and the former is dependent on ghrelin/GHS-R1a signaling while the latter may not always be. In addition, our findings suggested that GHS-R1a-dependent elevation in serum IL-6 might contribute to increased despair-like behavior in chronic CR state.

Guided, Fusion-Based, Large Depth-of-field 3D Imaging Using a Focal Stack.

Three dimensional (3D) imaging technology has been widely used for many applications, such as human-computer interactions, making industrial measurements, and dealing with cultural relics. However, existing active methods often require both large apertures of projector and camera to maximize light throughput, resulting in a shallow working volume in which projector and camera are simultaneously in focus. In this paper, we propose a novel method to extend the working range of the structured light 3D imaging system based on the focal stack. Specifically in the case of large depth variation scenes, we first adopted the gray code method for local, 3D shape measurement with multiple focal distance settings. Then we extracted the texture map of each focus position into a focal stack to generate a global coarse depth map. Under the guidance of the global coarse depth map, the high-quality 3D shape measurement of the overall scene was obtained by local, 3D shape-measurement fusion. To validate the method, we developed a prototype system that can perform high-quality measurements in the depth range of 400 mm with a measurement error of 0.08%.

Resonance Assignments of Lowly Populated and Unstable Enzyme Intermediate Complex under Real-Time Conditions.

Unstable and low-abundance protein complexes represent a large family of transient protein complexes that are difficult to characterize, even by means of high-resolution NMR spectroscopy. A method to assign the NMR signals of these unstable complexes through a combination of selective isotope labeling of amino acids in a protein and site-specific labeling the protein with a paramagnetic tag is presented herein. By using this method, the resonances of unstable thioester intermediate complex (lifetime <5 h and highest concentration ≈20 µm) generated by Staphylococcus aureus sortase A and its peptide substrate under a real-time reaction have been assigned.

A Novel Coumarin-Based Fluorescent Probe for the Detection of Hydrazine Both in Aqueous Solution and Vapor State.

A novel coumarin-based fluorescent probe CF was synthesized for the detection of hydrazine both in aqueous solution and vapor state with high sensitivity and selectivity. Upon addition of hydrazine, the solution of probe CF in MeCN-H2O (3/7, v/v, buffered CH3COOH/CH3COONa) at pH 5.0 exhibited a remarkable change in emission color from pale green to light blue, which could be recognized with naked eyes. Applied in weak acid condition, probe CF could detect hydrazine selectively with large amount of unknown environments according to the competing tests. Besides, with the limit of detection 8.32 ppb (2.6 × 10(-7) M), probe CF could well meet the request (10 ppb) of the U.S. Environmental Protection Agency (EPA).

A dansyl based fluorescence chemosensor for Hg(2+) and its application in the complicated environment samples.

We have developed a novel fluorescent chemosensor (DAM) based on dansyl and morpholine units for the detection of mercury ion with excellent selectivity and sensitivity. In the presence of Hg(2+) in a mixture solution of HEPES buffer (pH 7.5, 20 mM) and MeCN (2/8, v/v) at room temperature, the fluorescence of DAM was almost completely quenched from green to colorless with fast response time. Moreover, DAM also showed its excellent anti-interference capability even in the presence of large amount of interfering ions. It is worth noting that DAM could be used to detect Hg(2+) specifically in the Yellow River samples, which significantly implied the potential applications of DAM in the complicated environment samples.

A unique dansyl-based chromogenic chemosensor for rapid and ultrasensitive hydrazine detection.

We developed a new dansyl phthalimide-based fluorescent chemosensor for hydrazine detection. Upon a Gabriel type-based hydrazinolysis of dansyl phthalimide (DPI) in the presence of hydrazine in a mixture of HEPES buffer (pH 7.0, 20 mM) and DMSO (1/9, v/v) at room temperature, the chemosensor produces fluorescent dansyl-NH2 with the maximum emission wavelength changed from 475 nm to 512 nm along with a color change from yellow to colorless, allowing colorimetric detection of hydrazine by the naked eye. DPI can selectively detect hydrazine over other environmentally abundant ions. Moreover, DPI coated with silica gel TLC plates could act as a visual and fluorimetric probe for hydrazine vapor at a partial pressure of 5.5 × 10-3 mm Hg over other potentially interfering volatile analytes, including hydrogen peroxide, ethylenediamine, urea, ammonium hydroxide and methylamine. DPI can also be used for the detection of hydrazine in water samples and HeLa cells without appreciable interference from other biologically abundant analytes. The limit of detection is 6.01 ppb (1.88 × 10-7 M), which is well below the accepted limit (10 ppb) for hydrazine set by the U.S. Environmental Protection Agency (EPA).