Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host’s immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study’s results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host’s immunity.     

新颖的基于梯度投影法的混合指标动态避障算法

为解决在有动态障碍物环境下的避障问题, 针对七自由度冗余机械臂提出了一种实时避障方法, 该方法将传统复杂的机械臂避障规划转化为对单根连杆进行避障引导的运动规划. 通过连杆与障碍物的位置关系划分主次危险杆件, 并对杆件进行实时的避障规划, 引导机械臂在快速避开障碍物的同时向目标点运动. 在避障完成后, 基于自运动的逆解算法, 构建了安全距离势能指标确定自运动解集中的最优位形解并进行达点运动. 结果表明：该算法在动静态环境下进行达点运动时皆能及时有效地避开障碍物, 且避障过程中平均单步迭代运算时间约25 ms, 远小于传统避障算法, 验证了算法的实时性和有效性.

     

Microstructural evolution of a silicon carbide-carbon coated nanostructured ferritic alloy composite during in-situ Kr ion irradiation at 300℃ 450℃

This work focuses on irradiation behaviors of a novel silicon carbide and carbon coated nanostructured ferritic alloy (SiC-C@NFA) composite for potential applications as a cladding and structural material for next generation nuclear reactors.The SiC-C@NFA samples were irradiated with 1 MeV Kr ions up to 10 dpa at 300 and 450 ℃.Microstructures and defect evolution were studied in-situ at the IVEM-Tandem facility at Argonne National Laboratory.The effects of ion irradiation on various phases such as α-ferrite matrix,(Fe,Cr)7C3,and (Ti,W)C precipitates were evaluated.The α-ferrite matrix showed a continuous increase in dislocation density along with spatial ordering of dislocation loops (or loop strings) at ＞5 dpa.The size of the dislocation loops at 450 ℃ was larger than that at 300 ℃.The nucleation and growth of new (Ti,W)C precipitates in α-ferrite grains were enhanced with the ion dose at 450 ℃.This study provides new insight into the irradiation resistance of the SiC-C@NFA system.     

Shear analysis of rice husk ash (RHA) reinforced tin-0.7-copper composite solders on electroless nickel/immersion silver (ENIAg) surfaces

In this study, the mechanical performance of the rice husk ash-reinforced tin-0.7 copper composite solder was investigated. 0.01 wt.%, 0.05 wt.% and 0.1 wt.% of rice husk ash (RHA) were added to the solder matrix to prepare the composite solders. In order, to replace the costly electroless nickel immersion gold surface finish on the copper substrate, the effect of electroless nickel immersion silver (ENIAg) as the surface finish was studied. The differential scanning calorimetry (DSC) analysis showed that the composite solder exhibited lower melting temperature relative to the plain solder owing to the inclusion of rice husk ash. Shear strength analysis was carried out to investigate the influence of rice husk ash and electroless nickel immersion silver surface finish on the shear strength of the developed composite solders. The results proved that the rice husk ash failed to enhance the shear strength of tin-0.7 copper lead-free solder with the plain solder exhibiting the highest shear strength.     

A Dietary Oxysterol, 7-Ketocholesterol,Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice

Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.     

Membrane Targeting and GTPase Activity of Rab7 Are Required for Its Ubiquitination by RNF167

Rab7 is a GTPase that controls late endosome and lysosome trafficking. Recent studies have demonstrated that Rab7 is ubiquitinated, a post-translational modification mediated by an enzymatic cascade. To date, only one ubiquitin E3 ligase and one deubiquitinase have been identified in regulating Rab7 ubiquitination. Here, we report that RNF167, a transmembrane endolysosomal ubiquitin ligase, can ubiquitinate Rab7. Using immunoprecipitation and in vitro ubiquitination assays, we demonstrate that Rab7 is a direct substrate of RNF167. Subcellular fractionation indicates that RNF167 activity maintains Rab7′s membrane localization. Epifluorescence microscopy in HeLa cells shows that Rab7-positive vesicles are larger under conditions enabling Rab7 ubiquitination by RNF167. Characterization of its ubiquitination reveals that Rab7 must be in its GTP-bound active form for membrane anchoring and, thus, accessible for RNF167-mediated ubiquitin attachment. Cellular distribution analyses of lysosome marker Lamp1 show that vesicle positioning is independent of Rab7 and RNF167 expression and that Rab7 endosomal localization is not affected by RNF167 knockdown. However, both Rab7 and RNF167 depletion affect each other’s lysosomal localization. Finally, this study demonstrates that the RNF167-mediated ubiquitination of Rab7 GTPase is impaired by variants of Charcot–Marie–Tooth Type 2B disease. This study identified RNF167 as a new ubiquitin ligase for Rab7 while expanding our knowledge of the mechanisms underlying the ubiquitination of Rab7.     

The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage

P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.     

合金元素对A7N01铝合金组织及性能的影响

采用正交试验法设计出八种不同成分的A7N01铝合金,加工后通过光学显微镜观察合金铸锭的金相显微形貌;经自然时效一月后,借助拉伸试验机、SEM观察及EDS分析对合金的强度和塑性进行研究;并采用正交分析法中的极差分析法、方差分析法分析合金的力学性能。结果表明,微量元素Mn、Cr、Zr、Ti可细化合金铸锭晶粒,其作用依次是:Mn、Cr联合作用大于Ti大于Zr;合金的强度受Zn、Mg、Cu元素含量影响较大;合金的拉伸断口是以韧窝为主的韧性断裂,且断口中存在杂质元素Fe和Si。