TRIM50 promotes NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization.

Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.

αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway.

In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.

Selective deficiency of UCP-1 and adropin may lead to different subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

Tiam1 mediates Rac1 activation and contraction-induced glucose uptake in skeletal muscle cells.

Contraction-stimulated glucose uptake in skeletal muscle requires Rac1, but the molecular mechanism of its activation is not fully understood. Treadmill running was applied to induce C57BL/6 mouse hind limb skeletal muscle contraction in vivo and electrical pulse stimulation contracted C2C12 myotube cultures in vitro. The protein levels or activities of AMPK or the Rac1-specific GEF, Tiam1, were manipulated by activators, inhibitors, siRNA-mediated knockdown, and adenovirus-mediated expression. Activated Rac1 was detected by a pull-down assay and immunoblotting. Glucose uptake was measured using the 2-NBD-glucose fluorescent analog. Electrical pulse stimulated contraction or treadmill exercise upregulated the expression of Tiam1 in skeletal muscle in an AMPK-dependent manner. Axin1 siRNA-mediated knockdown diminished AMPK activation and upregulation of Tiam1 protein expression by contraction. Tiam1 siRNA-mediated knockdown diminished contraction-induced Rac1 activation, GLUT4 translocation, and glucose uptake. Contraction increased Tiam1 gene expression and serine phosphorylation of Tiam1 protein via AMPK. These findings suggest Tiam1 is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.

Bean-Pod-Inspired 3D-Printed Phase Change Microlattices for Solar-Thermal Energy Harvesting and Storage.

Effective and reliable encapsulation of phase change materials (PCMs) is essential and critical to the high-performance solar-thermal energy harvesting and storage. However, challenges remain pertaining to manufacturing scalability, high efficiency in energy storage/release, and anti-leakage of melted PCMs. Herein, inspired by natural legume, a facile and scalable extrusion-based core-sheath 3D printing strategy is demonstrated for directly constructing bean-pod-structured octadecane (OD)/graphene (BOG) phase change microlattices, with regular porous configuration as well as individual and effective encapsulation of OD "beans" into highly interconnected graphene network wrapping layer built by closely stacked and aligned graphene sheets. The unique architectural features enable the ready spreading of light into the interior of phase change microlattice, a high transversal thermal conductivity of 1.67 W m-1 K-1 , and rapid solar-thermal energy harvesting and transfer, thereby delivering a high solar-thermal energy storage efficiency, and a large phase change enthalpy of 190 J g-1 with 99.1% retention after 200 cycles. Most importantly, such encapsulated PCMs feature an exceptional thermal reliability and stability, with no leakage and shape variation even at 1000 thermal cycles and partial damage of BOG. This work validates the feasibility of scalably printing practical encapsulated PCMs, which may revolutionize the fabrication of composite PCMs for solar-thermal energy storage devices.

Transcriptome analysis of the Macrobrachium nipponense hepatopancreas provides insights into immunoregulation under Aeromonas veronii infection.

The oriental river prawn Macrobrachium nipponense is a commercially important freshwater shrimp that is widely farmed in China. Aeromonas veronii is a conditional pathogen of farmed shrimp, which has caused huge economic losses to the industry. Therefore, there is urgency to study the host-pathogen interactions between M. nipponense and A. veronii to screen individuals with antimicrobial resistance. In this study, we examined the hepatopancreas of moribund M. nipponense infected with A. veronii and healthy individuals at both the histopathological and transcriptomic levels. We showed that A. veronii infection resulted in tubular necrosis of the M. nipponense hepatopancreas. Such changes likely affect assimilation, storage, and excretion by the hepatopancreas, which could ultimately affect the survival and growth of infected individuals. Among the 61,345 unigenes obtained through RNA sequencing and de novo transcriptome assembly, 232 were differentially expressed between the two groups. KEGG and GO analyses revealed that these differentially expressed genes were implicated in pathways, including PPAR, PI3K/AKT, and AMPK signaling. The results of this study will contribute to an analysis of the immune response of M. nipponense to A. veronii infection at the transcriptomic level. Furthermore, the RNA-seq data generated here provide an important genomic resource for research on M. nipponense in the absence of a reference genome.

An AMPK/Axin1-Rac1 signaling pathway mediates contraction-regulated glucose uptake in skeletal muscle cells.

Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and liver kinase B1 during glucose starvation-dependent activation of AMPK. Here, we demonstrate that electrical pulse-stimulated (EPS) contraction of C2C12 myotubes or treadmill exercise of C57BL/6 mice enhanced reciprocal coimmunoprecipitation of Axin1 and AMPK from myotube lysates or gastrocnemius muscle tissue. Interestingly, EPS or exercise upregulated total cellular Axin1 levels in an AMPK-dependent manner in C2C12 myotubes and gastrocnemius mouse muscle, respectively. Also, direct activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide treatment of C2C12 myotubes or gastrocnemius muscle elevated Axin1 protein levels. On the other hand, siRNA-mediated Axin1 knockdown lessened activation of AMPK in contracted myotubes. Further, AMPK inhibition with compound C or siRNA-mediated knockdown of AMPK or Axin1 blocked contraction-induced GTP loading of Rac1, p21-activated kinase phosphorylation, and contraction-stimulated glucose uptake. In summary, our results suggest that an AMPK/Axin1-Rac1 signaling pathway mediates contraction-stimulated skeletal muscle glucose uptake.

Association between polymorphism in CDKN2B-AS1 gene and its interaction with smoking on the risk of lung cancer in a Chinese population.

BACKGROUND: Long non-coding RNAs became the hot spots in the carcinogenesis of various tumors. This case-control study evaluated the association between the rs2151280 in lncRNA CDKN2B-AS1 and lung cancer risk. METHODS: This study included 507 lung cancer patients and 542 healthy individuals. Odds ratios and their 95% confidence intervals were calculated by unconditional logistic regression analysis to evaluate the association between the rs2151280 and lung cancer risk. RESULTS: Compared with individuals carrying TT genotype, individuals carrying CC genotype of rs2151280 had a decreased risk of lung cancer (OR = 0.640, 95%CI = 0.421-0.972, P = 0.036). In the recessive model, rs2151280 CC genotype was observed to reduce the risk of lung cancer (OR = 0.684). C allele was associated with non-small cell lung cancer risk (OR = 0.674). The rs2151280 was significantly associated with lung adenocarcinoma risk (CCvsTT: OR = 0.567, 95%CI = 0.333-0.965, P = 0.037; CCvsTC+TT: OR = 0.543, 95%CI 0.330-0.893, P = 0.016, respectively). However, there was no significant association between rs2151280 and lung squamous cell carcinoma risk in five models. The quantitative analysis suggested that there were no significant interactions of rs2151280 with smoking exposure to lung cancer susceptibility. CONCLUSIONS: This hospital-based case-control study suggested that CDKN2B-AS1 rs2151280 T>C was associated with the risk of lung cancer.

Evaluate performance of the Abbott chemiluminescent microparticle immunoassay assay for detection of syphilis infection in Chinese blood donors.

BACKGROUND AND OBJECTIVES: To prevent Treponema Pallidum (TP) transmission from blood transfusion, enzyme-linked immunosorbent assay (EIA) for anti-TP has been widely used in routine blood donation screening in China for many years. The aim of this study was to evaluate the performance of the Abbott CMIA assay for detection of anti-TP in Chinese blood donors. MATERIALS AND METHODS: A total of 2420 plasma samples, already routinely screened for anti-TP by two different EIAs, from four blood Centers were tested for anti-TP by Abbott CMIA. Subsequently, all samples with positive results by one or both EIAs and/or by Abbott CMIA were subjected to confirmatory testing (CT) using recombinant immunoblot assay (RIBA) or Treponema Pallidum particle agglutination assay (TPPA). TP infection was defined by a RIBA or TPPA positive. RESULTS: Compared with two EIAs strategy, Abbott CMIA showed a relatively best sensitivity as 98.80% (95% CI: 97.44%-100.16%) and a relatively best specificity as 99.58% (95% CI: 99.30%-99.85%), yielding the best consistency (99.49%) between anti-TP CT results with the highest κ value of .98. CONCLUSION: This is the first study to evaluate the performance of the Abbott CMIA assays for detection of syphilis in Chinese blood donors. Our results suggested that CMIA performed better than both EIAs, and implementation of CMIA replacing two different EIA reagents might help to further reduce the risk of transfusion-transmitted TP infection, decrease unnecessary blood waste and loss of blood donors.

Evodiamine inhibits migration and invasion by Sirt1-mediated post-translational modulations in colorectal cancer.

Colorectal cancer (CRC) is one of the most difficult cancers to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidences show that Evodiamine (EVO) exerts an inhibitory effect on cancer cell apoptosis, migration, and invasion. In this study, we investigated the effects of EVO on the metastasis of CRC cells in vitro and in vivo. In vitro, wound-healing and transwell assay showed that migration and invasion of HT-29 and HCT-116 CRC cells were inhibited significantly by EVO. Western blot and RT-PCR showed that EVO reduced the expression of matrix metalloproteinase-9 in a dose-dependent manner. In EVO-induced cells, the intracellular NAD+/NADH ratio was increased, the level of Sirt1 was increased, and acetyl-NF-κB P65 was decreased. This process was inhibited by nicotinamide, an inhibitor of Sirt1. In vivo, EVO reduced tumor metastasis markedly. These findings provide evidences that EVO suppresses the migration and invasion of CRC cells by inhibiting the acetyl-NF-κB p65 by Sirt1, resulting in suppression of metalloproteinase-9 expression in vitro and in vivo.

Clinicopathological and prognostic significance of long noncoding RNA MALAT1 in human cancers: a review and meta-analysis.

BACKGROUND: The aberrant regulation of MALAT1 has been indicated to be involved in various carcinogenic pathways contributing to the tumourigenesis and progression of cancers. The current meta-analysis summarized the research advances of MALAT1 functions and analyzed its prognostic value among multiple types of cancers. METHODS: Eligible studies were identified through retrieving the PubMed, Web of Science, and CNKI databases, up to Mar 1, 2018. 28 studies of 5436 patients and 36 studies of 3325 patients were enrolled in the meta-analysis to evaluate the association of MALAT1 expression with survival outcomes and clinical parameters. RESULTS: The results demonstrated that over-expression of MALAT1 may predict lymph node metastasis (pooled OR = 2.335, 95% CI 1.606-3.395, P = 0.000) and distant metastasis (pooled OR = 2.456, 95% CI 1.407-4.286, P = 0.002). Moreover, MALAT1 was also related with tumour size (pooled OR = 1.875, 95% CI 1.257-2.795, P = 0.002) and TNM stage (pooled OR = 2.034, 95% CI 1.111-3.724, P = 0.021). Additionally, elevated MALAT1 expression could predict poor OS (pooled HR = 2.298, 95% CI 1.953-2.704, P = 0.000), DFS (pooled HR = 2.036, 95% CI 1.240-3.342, P = 0.005), RFS (pooled HR = 2.491, 95% CI 1.505-4.123, P = 0.000), DSS (pooled HR = 2.098, 95% CI 1.372-3.211, P = 0.001) and PFS (pooled HR = 1.842, 95% CI 1.138-2.983, P = 0.013) in multivariate model. Importantly, subgroup analyses disclosed that increased MALAT1 expression had a poor OS among different cancer types (Estrogen-dependent cancer: pooled HR = 2.656, 95% CI 1.560-4.523; urological cancer: pooled HR = 1.952, 95% CI 1.189-3.204; glioma: pooled HR = 2.315, 95% CI 1.643-3.263; digestive cancer: pooled HR = 2.451, 95% CI 1.862-3.227). CONCLUSIONS: The present findings demonstrated that MALAT1 may be a novel biomarker for predicting survival outcome, lymph node metastasis and distant metastasis.

Polymorphism in lncRNA AC016683.6 and its interaction with smoking exposure on the susceptibility of lung cancer.

BACKGROUND: Long non-coding RNAs play pivotal roles in the carcinogenesis of multiple types of cancers. This study is firstly to evaluate influence of rs4848320 and rs1110839 polymorphisms in long non-coding RNA AC016683.6 on the susceptibility of lung cancer. METHODS: The present study was a hospital-based case-control study with 434 lung cancer patients and 593 cancer-free controls. Genotyping of the two SNPs detected by Taqman® allelic discrimination method. RESULTS: There were no statistically significant associations between rs4848320 and rs1110839 polymorphisms in AC016683.6 and risk of lung cancer in overall population. However, in the smoking population, rs4848320 and rs1110839 polymorphisms significantly increased the risk of lung cancer in dominant and homozygous models (Rs4848320: P = 0.029; Rs1110839: P = 0.034), respectively. In male population, rs1110839 genetic variant was related to the risk of lung cancer in all genetic models (GG vs. TT: P = 0.008; Dominant model: P = 0.029; Recessive model: P = 0.027) rather than heterozygous model. The crossover analyses provided rs4848320 and rs1110839 risk genotypes carriers combined with smoking exposure 2.218-fold, 1.755-fold increased risk of lung cancer (Rs4848320: P = 0.005; Rs1110839: P = 0.017). Additionally, there were significantly positive multiplicative interaction of rs4848320 polymorphism with smoking status, with adjusted OR of 2.244 (1.162-4.334), but rs1110839 polymorphism did not exist. CONCLUSIONS: Rs4848320 and rs1110839 polymorphisms may be associated with lung cancer susceptibility. Interaction of rs4848320 risk genotypes with smoking exposure may strengthen the risk effect on lung cancer.

Artesunate enhances γδ T-cell-mediated antitumor activity through augmenting γδ T-cell function and reversing immune escape of HepG2 cells.

OBJECTIVE: To explore the effect and mechanism of artesunate on γδ T cell-mediated antitumor immune responses against hepatoma carcinoma cells (HepG2) in vitro. METHODS: Human γδ T cells or HepG2 were respectively treated with artesunate, subjected to co-culture as appropriate, and the following assays were subsequently conducted: CCK8 to examine cell viability; LDH release assay to detect the killing effect of γδ T cells on HepG2 cells; flow cytometry to examine the expression of perforin (PFP) and granzyme B (GraB) of γδ T cells; ELISA to evaluate the levels of TGF-ß1 and IL-10 in the collected supernatant of HepG2 cells pretreated with artesunate; and Western blot analysis to examine Fas, FasL, STAT3, p-STAT3 expression of HepG2 cells induced by artesunate. Results: The results showed that the cytotoxicity effect of γδ T cells pretreated with artesunate on HepG2 cells was augmented via elevating the expression of GraB in γδ T cells. Furthermore, treatment with artesunate reversed the inhibition of HepG2 cells on γδ T cells by reducing the secretion of TGF-ß1 in HepG2 cells supernatant and enhanced the antitumor effect of γδ T cells against HepG2 cells through increasing the expression of Fas on HepG2 cells, which may be attributed to the inhibition of STAT3 signaling protein. CONCLUSION: Artesunate has several mechanisms for augmenting the antitumor immune responses mediated by γδ T cells. These results suggested artesunate may be an efficacious agent in the treatment of hepatocellular carcinoma.

Long non-coding RNA HOTAIR polymorphism and susceptibility to cancer: an updated meta-analysis.

BACKGROUND: An increasing number of publications are drawing attention to the associations between six common polymorphisms in HOX transcript anti-sense RNA (HOTAIR) and the risk of cancers, while these results have been controversial and inconsistent. We conducted an up-to-date meta-analysis to pool eligible studies and to further explore the possible relationships between HOTAIR polymorphisms (rs920778, rs7958904, rs12826786, 4,759,314, rs874945, and rs1899663) and cancer risk. METHODS: A systematic retrieval was conducted up to 1 July 2017 in the PubMed, Web of Science, and CNKI databases. Eighteen eligible publications including 45 case-control studies with 58,601subjects were enrolled for assessing the associations between the 6 polymorphisms in HOTAIR and cancer risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed to reveal the polymorphisms and susceptibility to cancer. All the statistical analyses were performed using STATA 11.0 software. RESULTS: The pooled analyses detected significant associations between the rs920778 polymorphism and increased susceptibility to cancer in recessive, dominant, allelic, homozygous, and heterozygous models. For the rs7958904 polymorphism, we obtained the polymorphism significantly decreased susceptibility to overall cancer risk among five genetic models rather than recessive and homozygous models. For the rs12826786 polymorphism, we identified it significantly increased susceptibility to cancer risk in all genetic models rather than heterozygous models. However, no significant association was found between the rs1899663, rs874945, and rs4759314 polymorphisms and susceptibility of cancer. CONCLUSION: These findings of the meta-analysis suggest that HOTAIR polymorphism may contribute to cancer susceptibility.

The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension.

Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls (P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different (P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation-coagulation-thrombosis cycle.

IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity.

Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.

cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity.

Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

A putative transglycosylase encoded by SCO4132 influences morphological differentiation and actinorhodin production in Streptomyces coelicolor.

Here we report that tgdA, a novel gene encoding a putative transglycosylase, affects both the morphological differentiation and the yield of blue-pigmented compound actinorhodin in Streptomyces coelicolor. The tgdA null mutant displays sparse aerial hyphae and irregular spore chains frequently lacking chromosomal DNA. Elevated actinorhodin production coincides with the overexpression of actII-orf4 in mutant. tgdA expression is temporally and developmentally regulated. The tgdA orthologs in Streptomyces avermilitis and Streptomyces lividans also affect differentiation.

Analysis of risk factors of lower extremity deep venous thrombosis in patients undergoing hepatobiliary surgery.

This study analyzed records of 200 patients who underwent hepatobiliary surgery to identify factors that contribute to lower extremity venous thromboembolism (VTE). 19 patients (9.50%) developed lower extremity deep vein thrombosis. Univariate analysis revealed significant differences between the study group and the control group in terms of age, body mass index, previous thromboembolic history, hypertension, type 2 diabetes, hyperlipidemia, smoking history, times of lower extremity venipuncture, operation time, postoperative bedrest time, postoperative platelet count, postoperative D-dimer level, and postoperative C-reactive protein level (P<0.05). Multivariable logistic regression analysis identified age ≥60 years, body mass index ≥24 kg/m2, previous history of thromboembolism, hypertension, type 2 diabetes mellitus, hyperlipidemia, smoking history, number of lower extremity venipunctures ≥5, operation time ≥2 hours, postoperative bedrest time ≥48 hours, postoperative blood platelet count ≥300×109/L, postoperative D-dimer level ≥200 g/L, and postoperative C-reactive protein ≥8.0 mg/L as significant predisposing factors for lower extremity VTE. The study concludes that patients undergoing hepatobiliary surgery are at an increased risk of developing lower extremity VTE, and prevention strategies must be tailored to each patient's unique set of risk factors. This includes careful management of postoperative bed rest, monitoring of platelet count, D-dimer and C-reactive protein levels, controlling hypertension, type 2 diabetes mellitus, hyperlipidemia, and cessation of smoking. This study highlights the importance of early identification of patients at high risk of lower extremity VTE following hepatobiliary surgery and comprehensive prevention measures.

MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria.

Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear etiopathogenesis. While ageing, oxidative stress, metabolic disorders, and mitochondrial dysfunction have been proposed as potential contributors to the development of PF, effective treatments for this condition remain elusive. However, Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a peptide encoded by the mitochondrial genome, has shown promising effects on glucose and lipid metabolism, cellular and mitochondrial homeostasis, as well as the reduction of systemic inflammatory responses, and is being investigated as a potential exercise mimetic. Additionally, dynamic expression changes of MOTS-c have been closely linked to ageing and ageing-related diseases, indicating its potential as an exercise mimetic. Therefore, the review aims to comprehensively analyze the available literature on the potential role of MOTS-c in improving PF development and to identify specific therapeutic targets for future treatment strategies.