NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

SIW-Based Devices

With the development of microwave wireless communication technology, microwave passive frequency selectivity circuits are developing toward multi-function and miniaturization. Substrate-integrated waveguide (SIW) devices have good development prospects in miniaturization and integration. The research on devices based on SIW is lack unified theoretical combing. This chapter describes the novel circuits based on substrate-integrated waveguide, including filter, power divider, switch, phase shifter, diplexer, and crossover. This chapter describes the design methods and special properties of these circuits. The display of these circuits is expected to give some inspiration to your research

C3HC4-type RING finger protein NbZFP1 is involved in growth and fruit development in Nicotiana benthamiana.

C3HC4-type RING finger proteins constitute a large family in the plant kingdom and play important roles in various physiological processes of plant life. In this study, a C3HC4-type zinc finger gene was isolated from Nicotiana benthamiana. Sequence analysis indicated that the gene encodes a 24-kDa protein with 191 amino acids containing one typical C3HC4-type zinc finger domain; this gene was named NbZFP1. Transient expression of pGDG-NbZFP1 demonstrated that NbZFP1 was localized to the chloroplast, especially in the chloroplasts of cells surrounding leaf stomata. Virus-induced gene silencing (VIGS) analysis indicated that silencing of NbZFP1 hampered fruit development, although the height of the plants was normal. An overexpression construct was then designed and transferred into Nicotiana benthamiana, and PCR and Southern blot showed that the NbZFP1 gene was successfully integrated into the Nicotiana benthamiana genome. The transgenic lines showed typical compactness, with a short internode length and sturdy stems. This is the first report describing the function of a C3HC4-type RING finger protein in tobacco

Puerarin suppresses the hepatic gluconeogenesis via activation of PI3K/Akt signaling pathway in diabetic rats and HepG2 cells

Pueraria, a Chinese herbal medicine, plays an important role in many classic prescriptions for the treatment of diabetes. Puerarin is the main component of pueraria. The current in vivo and in vitro research mainly focus on exploring the potential mechanism of puerarin in inhibiting hepatic gluconeogenesis. The type 2 diabetic rats were established by a combination of small dosage of streptozotocin (STZ) injection with high-fat diet. After the administration of puerarin 4 weeks, the parameters of the glucose and lipid metabolism were determined. HepG2 cells were treated by palmitic acid (PA) to induce the insulin resistance in vitro model. After the treatment of puerarin, the glucose consumption and cell viability were examined. Then, the protein expression of PI3K, Akt, pAkt, pFOXO1, FOXO1, PEPCK and G6pase in liver tissue and HepG2 cells were evaluated by western blot. RT-PCR was used to measure the content of PEPCK, G6pase mRNA in liver tissue. The results showed that puerarin administration significantly decrease the level of FBG, HbA1C and triglycerides in diabetic rats. Mechanistic research showed that puerarin activating PI3K/Akt is puerarin-mediated beneficial effects and can be reversed by inhibitor of PI3K or Akt. In conclusion, puerarin inhibits hepatic gluconeogenesis by activating PI3K/Akt signaling pathway

Concentrated growth factor combined with iRoot BP Plus promotes inflamed pulp repair: an in vitro and in vivo study

Abstract Background Platelet concentrates combined with calcium silicate cements may promote reparative dentin formation. However, few studies have reported their effect on dental pulp inflammation. This study aimed to evaluate the effects of concentrated growth factor (CGF) combined with iRoot BP Plus on inflammatory human dental pulp stem cells (hDPSCs) in vitro and inflamed pulp in rats in vivo. Methods The proliferation of LPS-stimulated hDPSCs treated with 50% CGF with/without 25% iRoot BP Plus was evaluated using Cell Counting Kit-8 on days 1, 4 and 7. The expression of genes associated with inflammation on day 1 and differentiation on day 14 was analysed by real-time polymerase chain reaction. The exposed pulp of rat maxillary molars was injected with 10 mg/mL LPS and directly capped with CGF membrane with/without iRoot BP Plus extract for 1, 7 and 28 days. The teeth were subjected to histologic analyses and immunohistochemistry. Results The proliferation rates of the inflammatory hDPSCs after the combination treatment were significantly higher than those after the other treatments on days 4 and 7 (P < 0.05). IL-1β, IL-6, and TNF-α levels were increased in inflammatory hDPSCs but decreased after treatment with CGF combined with iRoot BP Plus extract, whereas IL-4 and IL-10 showed the opposite expression patterns. Expression of the odontogenesis-related genes OCN, Runx2, and ALP was dramatically enhanced by combined treatment with CGF and iRoot BP Plus extract. In rat pulp, the average inflammation scores of the CGF and CGF-iRoot BP Plus groups significantly decreased in comparison with those of the LPS group (P < 0.05), and the CGF-iRoot BP Plus group had more reparative dentin than the CGF and BP groups. Immunohistochemical staining showed fewer M1 macrophages on day 1 and more M2 macrophages on day 7 in the CGF-iRoot BP Plus group than in the other groups. Conclusions The combination of CGF and iRoot BP Plus showed a synergistic effect on anti-inflammatory potential and promoted greater pulp healing than CGF or iRoot BP Plus alone

Effects of Nitrogen Conservation Measures on the Nitrogen Uptake by Cotton Plants and Nitrogen Residual in Soil Profile in Extremely Arid Areas of Xinjiang, China

This study researched the effects of using various nitrogen (N) conservation measures on the residual characteristics of nitrate and ammonium N in soil and the associated N uptake by cotton plants. A field experiment with six treatments was conducted, as follows, no N application (DT1), conventional N application (DT2), 60% conventional N application combined with DCD (DT3), 60% conventional N application combined with NBPT (DT4), 60% conventional N application combined with cotton straw returning (DT5), and 60% conventional N application combined with DCD, NBPT, and cotton straw returning (DT6). The results showed that the cotton straws in the DT5 treatment were beneficial for the vegetative growth of cotton seedlings. However, it was observed that the later performance of the plants in this sample was poor in terms of height, biomass, and yield of cotton. The plant height in the DT6 sample increased by 15 cm compared with those in DT1, and the soil and plant analyzer development (SPAD) values of the fourth leaf from the top of the DT6 plants were higher than those in the DT1 and DT4 samples. The DT6 plants (60% Urea + DCD + NBPT + cotton straw) increased N use efficiency by up to 47%, and no significant decrease in biomass and cotton yield was observed compared to the DT2 sample. The residual content of nitrate N in the tillage layer increased gradually over time between two rounds of drip irrigation treatment applications. Compared with the DT2 treatment, the other treatments resulted in lower residual nitrate N contents. In summary, the application of N fertilizers at a reduced rate combined with N conservation measures may increase N use efficiency and decrease the risk of non-point source N fertilizer pollution, while maintaining the cotton yield

Crystal Structure Analysis and the Identification of Distinctive Functional Regions of the Protein Elicitor Mohrip2

The protein elicitor MoHrip2, which was extracted from Magnaporthe oryzae as an exocrine protein, triggers the tobacco immune system and enhances blast resistance in rice. However, the detailed mechanisms by which MoHrip2 acts as an elicitor remain unclear. Here, we investigated the structure of MoHrip2 to elucidate its functions based on molecular structure. The 3-dimensional structure of MoHrip2 was obtained. Overall, the crystal structure formed a β-barrel structure and showed high similarity to the pathogenesis-related (PR) thaumatin superfamily protein thaumatin-like xylanase inhibitor (TL-XI). To investigate the functional regions responsible for MoHrip2 elicitor activities, the full length and 8 truncated proteins were expressed in Escherichia coli and were evaluated for elicitor activity in tobacco. Biological function analysis showed that MoHrip2 triggered the defense system against Botrytis cinerea in tobacco. Moreover, only MoHrip2M14 and other fragments containing the 14 amino acids residues in the middle region of the protein showed the elicitor activity of inducing a hypersensitive response and resistance related pathways, which were similar to that of full-length MoHrip2. These results revealed that the central 14 amino acid residues were essential for anti-pathogenic activity