Aquaporins (AQPs) are a class of highly conserved integral membrane proteins that facilitate the uptake and transport of water and other small molecules across cell membranes.However, little is known about AQP genes in pomegranate (Punica granatum L.) and their potential role in water accumulation of the outer seed coat.We identified 38 PgrAQP genes in the pomegranate genome and divided them into five subfamilies based on a comparative analysis.Purifying selection played a role in the evolution of PgrAQP genes and a whole-genome duplication event in Myrtales may have contributed to the expansion of PgrTIP, PgrSIP, and PgrXIP genes.Transcriptome data analysis revealed that the PgrAQP genes exhibited different tissue-specific expression patterns.Among them, the transcript abundance of PgrPIPs were significantly higher than that of other subfamilies.The mRNA transcription levels of PgrPIP1.3,PgrPIP2.8, and PgrSIP1.2 showed a significant linear relationship with water accumulation in seed coats, indicating that PgrPIP1.3/PgrPIP2.8 located in the plasma membrane and PgrSIP1.2 proteins located on the tonoplast may be involved in water accumulation and contribute to the cell expansion of the outer seed coat, which then develops into juicy edible flesh.Overall, our results provided not only information on the characteristics and evolution of PgrAQPs, but also insights on the genetic improvement of outer seed coats.
This paper introduces international trade in intermediate inputs into Clarida et al.(2002) to examine the welfare gains from monetary policy cooperation when the world is hit by cost-push shocks. We find that Clarida et al.(2002)'s prediction is right. Specifically, the introduction of the international trade in intermediate inputs opens a new channel through which the terms of trade at the stage of intermediate-goods production produce the spillover effect. In Clarida et al. (2002), the risk sharing effect and the terms of trade effect cancel out and the welfare gains from monetary policy cooperation disappear when the utility function of consumption is logarithmic. By contrast, in our model, the new channel still works. By internalizing the spillover effect produced through the new channel, the cooperative monetary policymaker achieves the welfare gains which are substantially larger than those found in the literature. In addition, we find that the welfare gains increase with the degree of intermediate-goods trade openness.
Ammonium (NH4+) is a key nitrogen source supporting plant growth and development. Proteins in the ammonium transporter (AMT) family mediate the movement of NH4+ across the cell membrane. Although several studies have examined AMT genes in various plant species, few studies of the AMT gene family have been conducted in chili pepper.Here, a total of eight AMT genes were identified in chili pepper, and their exon/intron structures, phylogenetic relationships, and expression patterns in response to arbuscular mycorrhizal (AM) colonization were explored. Synteny analyses among chili pepper, tomato, eggplant, soybean, and Medicago revealed that the CaAMT2;1, CaAMT2.4, and CaAMT3;1 have undergone an expansion prior to the divergence of Solanaceae and Leguminosae. The expression of six AMT2 genes was either up-regulated or down-regulated in response to AM colonization. The expression of CaAMT2;1/2;2/2;3 and SlAMT2;1/2;2/2;3 was significantly up-regulated in AM fungi-inoculated roots. A 1,112-bp CaAMT2;1 promoter fragment and a 1,400-bp CaAMT2;2 promoter fragment drove the expression of the β-glucuronidase gene in the cortex of AM roots. Evaluation of AM colonization under different NH4+ concentrations revealed that a sufficient, but not excessive, supply of NH4+ promotes the growth of chili pepper and the colonization of AM. Furthermore, we demonstrated that CaAMT2;2 overexpression could mediate NH4+ uptake in tomato plants.In sum, our results provide new insights into the evolutionary relationships and functional divergence of chili pepper AMT genes. We also identified putative AMT genes expressed in AM symbiotic roots.
Porcine reproductive and respiratory syndrome (PRRS) is one of the most ruinous diseases in pig production. Our previous work showed that Tongcheng pigs (TC) were less susceptible to PRRS virus (PRRSV) than Large White (LW) pigs. To elucidate the difference in PRRSV resistance between the two breeds, small RNA-seq and ribo-zero RNA-seq were used to identify differentially expressed non-coding RNAs (including miRNAs and lincRNAs) responded to PRRSV in porcine alveolar macrophages (PAMs) from TC and LW pigs. Totally, 250 known mature miRNAs were detected. For LW pigs, there were 44 down-regulated and 67 up-regulated miRNAs in infection group; while for TC pigs, 12 down-regulated and 23 up-regulated miRNAs in TC infection group were identified. The target genes of the common differentially expressed miRNAs (DEmiRNAs) in these two breeds were enriched in immune-related processes, including apoptosis process, inflammatory response, T cell receptor signaling pathway and so on. In addition, 5 shared DEmiRNAs (miR-181, miR-1343, miR-296-3p, miR-199a-3p and miR-34c) were predicted to target PRRSV receptors, of which miR-199a-3p was validated to inhibit the expression of CD151. Interestingly, miR-378 and miR-10a-5p, which could inhibit PRRSV replication, displayed higher expression level in TC control group than that in LW control group. Contrarily, miR-145-5p and miR-328, which were specifically down-regulated in LW pigs, could target inhibitory immunoreceptors and may involve in immunosuppression caused by PRRSV. This indicates that DEmiRNAs are involved in the regulation of the immunosuppression and immune escape of the two breeds. Furthermore, we identified 616 lincRNA transcripts, of which 48 and 30 lincRNAs were differentially expressed in LW and TC pigs, respectively. LincRNA TCONS_00125566 may play an important role in the entire regulatory network, and was predicted to regulate the expression of immune-related genes through binding with miR-1343 competitively. In conclusion, this study provides an important resource for further revealing the interaction between host and virus, which will specify a new direction for anti-PRRSV research.
Abstract T-cell exhaustion is defined as T-cell dysfunction leading to loss of effector T-cells function. Restoring exhausted T-cells with agonistic anti-4-1BB monoclonal antibody is a promising strategy for cancer treatment. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a classical target with specific expression profiles in tumors. It has limited expression in normal adult tissues, but is overexpressed in multiple types of cancer, especially in colorectal carcinoma and non-small cell lung cancer. Here, we reported a novel bispecific antibody, LM-24C5 that specifically activates 4-1BB in a CEACAM5-dependent manner with localized T cell activation and reduced systemic toxicity. LM-24C5 was developed by introducing qualified 4-1BB heavy-chain variable into a human IgG1 CEACAM5 monoclonal antibody with disabled FcgR-mediated function. LM-24C5 was evaluated for its binding activity to human CEACAM5 and 4-1BB through protein and cell-based assays. The binding activity of LM-24C5 to tumor cells endogenously expressing CEACAM5 and activated primary T cells was confirmed. LM-24C5 was further evaluated in 4-1BB signalling reporter and co-culture assay with human peripheral blood mononuclear cells (PBMC). In vivo anti-tumor activity of LM-24C5 was assessed in hu4-1BB knock-in mice implanted with colon cancer cell line MC38 overexpressing huCEACAM5. Percentage of tumor infiltrating T cells and central memory CD8+ T cells were evaluated by FACS analysis. In addition, 2-week repeated dose toxicity study of LM-24C5 was conducted in hu4-1BB/4-1BBL double-transgenic mice. LM-24C5 efficiently bound to huCEACAM5-postitive cells (EC50: 3.78 nM) and activated human primary T cells. It induced superior 4-1BB activity (EC50: 1.07 nM) than benchmark antibody Urelumab (EC50: 3.38 nM) in the presence of cells expressing CEACAM5. The strength of 4-1BB activation induced by LM-24C5 was correlated with CEACAM5 expression levels. LM-24C5 was also found to stimulate T-cell activation (CD4+ EC50: 0.471, CD8+: 0.482) in PBMCs in a CEACAM5-dependent manner leading to significant IFN-γ production. Injection of LM-24C5 led to complete tumor regression around one month post treatment. Moreover, the tumor-free mice were resistant to tumor rechallenge, suggesting that LM-24C5 can induce long-term protective immunological memory. We have also observed that LM-24C5 increased tumor infiltrating lymphocytes and percentage of central memory CD8+ T cells in spleens. LM-24C5 was well tolerated in hu4-1BB/4-1BBL double-transgenic mice at a dose of 100mg/kg given once weekly for 2 weeks. In summary, LM-24C5 is a novel CEACAM5 dependent 4-1BB bispecific agonist antibody that could redirect and activate T cells to CEACAM5 positive tumor cells by engaging 4-1BB antigen, thus positioned as a potential novel therapy for colorectal carcinoma and other CEACAM5 positive tumors. Citation Format: Wei Cao, Jianjian Liu, Wentao Huang, Junwei Yang, Lei Shi, Yuan Li, Te Du, Xia Qin, Da Fei, Runsheng Li. Pre-clinical efficacy and toxicity profile of LM-24C5: A novel CEACAM5 x 4-1BB bispecific antibody in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2650.
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