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关键词： HLA   HLA-DQA1*05:05:24   next-generation sequencing   novel allele  

摘要： HLA-DQA1*05:05:24 differs from HLA-DQA1*05:05:01 by one synonymous nucleotide in codon 27 in Exon 2.

关键词： ciliary neurotrophic factor   astrocytes   IL-6/IL-6R   neuroinflammation   neuron  

摘要： The occurrence of epilepsy is a spontaneous and recurring process due to abnormal neuronal firing in the brain. Epilepsy is understood to be caused by an imbalance between excitatory and inhibitory neurotransmitters in the neural network. The close association between astrocytes and synapses can regulate the excitability of neurons through the clearance of neurotransmitters. Therefore, the abnormal function of astrocytes can lead to the onset and development of epilepsy. The onset of epilepsy can produce a large number of inflammatory mediators, which can aggravate epileptic seizures, leading to a vicious cycle. Neurons and glial cells interact to promote the onset and maintenance of epilepsy, but the specific underlying molecular mechanisms need to be further studied. Ciliary neurotrophic factor (CNTF) belongs to the IL-6 cytokine family and is mainly secreted by astrocytes and Schwann cells. In the normal physiological state, CNTF levels are low, but in an epileptic state, CNTF levels in the serum and tears of patients are elevated. Astrocyte activation plays an important role in epileptic seizures. CNTF activates astrocytes to produce a variety of secreted proteins, which are secreted into the astrocyte culture medium (ACM), thus forming a distinct culture medium (CNTF-ACM) that can be used to study the effect of astrocytes on neurons in vitro. CNTF-activated astrocytes increase the secretion of the pro-inflammatory factor IL-6. In the present study, CNTF-ACM was applied to primary cerebral cortical neurons to observe the specific effects of IL-6 in CNTF-ACM on neuronal activity and excitability. The results suggested that CNTF-ACM can reduce neuronal activity via the IL-6/IL-6R pathway, promote neuronal apoptosis, increase Ca2+ inflow, activate the large conductance calcium-activated potassium channel and enhance neuronal excitability. The results of the present study further revealed the functional changes of astrocytes after CNTF activated astrocytes and the e

关键词： heterogeneity   osteoarthritis   osteogenic and chondrogenic potential   single-cell RNA sequencing  

摘要： The heterogeneity of human umbilical cord mesenchymal stem cells (hUC-MSCs) is culturing-dependent, resulting in functional non-uniformness. To achieve the best clinical benefit, a comprehensive understanding of the origin of the heterogeneity in different culture systems can identify functional subgroups to direct the precise application of hUC-MSCs. Here, we create a single-cell transcriptome atlas of hUC-MSC in different culture systems for the identification of a subgroup of Ultroser-G-MSCs with high osteogenic and chondrogenic potentials featured by high expressions of IL1R1 and PDGFRA. Further experimental validations surprisingly reveal that IL1R1highPDGFRAhigh Ultroser-G-MSCs possess advantages over "traditional" hUC-MSCs in the treatments of modeled osteoarthritis, leading to a cell-cell communication network centered in Clusters 0 and 2. Moreover, we found that Wnt5 signaling is the key pathway for the dynamic transformation of osteogenic and chondrogenic phenotypes in hUC-MSC. Overall, the present study paves the way for the clarification of heterogenetic nature of hUC-MSC in different culture systems for the selection of optimal MSC types to achieve the precision on clinical treatments.

关键词： STING agonist   MSA-2   Lipid nanoparticles   Circular IL-23 mRNA   Platinum-modified MSA-2 (MSA-2-Pt)  

摘要： A next-generation STING agonist MSA-2 is a promising tumor immunotherapy strategy. However, the methods for improving the anti-tumor efficacy of MSA-2 are a lot of effort. We have demonstrated antitumor effect of platinum-modified MSA-2 (MSA-2-Pt) was better than MSA-2. Here, we combined lipid nanoparticles delivering circular IL-23 mRNA (LNP@cIL-23) and MSA-2-Pt strategy, which showed good antitumor efficacy. Firstly, we synthesized a new series of ionizable phospholipids and formulated and optimized an LNP36 for delivering circular IL-23 mRNA. Then, the combination of LNP36@cIL-23 mRNA and MSA-2-Pt induced tumor cell death and immune activation in the tumor with a single i.t. injection. Finally, the combination of LNP36@cIL-23 mRNA and MSA-2-Pt significantly decreased the melanoma B16F10 tumor and prolonged the survival, demonstrating significant anti-tumor effects. This finding provides promising new avenues for STING activation strategies in tumor immunotherapy.

关键词： Classical swine fever virus   E2 subunit vaccine   IL-28B  

摘要： The E2 subunit vaccine has been considered a promising alternative to an attenuated classical swine fever (CSF) vaccine. However, it fails to induce a good cellular immune response. Given that immunogenic adjuvants can regulate the cellular immunity to achieve a maximum efficacy against antigens, immunostimulatory effects of porcine IL-28B on the CSF virus (CSFV) E2 subunit vaccine were evaluated in the present study. We expressed recombinant proteins E2-IL28B, E2, and IL-28B using CHO-S mammalian cells as an antigen expression platform, and three types of CSFV E2 subunit vaccines based on antigens E2-IL28B, E2 + IL-28B, and E2 were prepared, respectively. We found that both E2-IL28B and E2 + IL-28B antigens exhibited superior immunogenicity with dramatically induced antibody titers and neutralizing antibody levels than the E2 alone. Moreover, E2-IL28B or E2 + IL-28B, instead of E2, boosted cellular immune responses via obviously increasing the percentages of CD3(+)CD4(+) T lymphocytes, promoting the lymphocyte proliferations, and enhancing the release of Th1-type cytokines. All results revealed that the inclusion of IL-28B, whether fused or mixed with E2, significantly elevated E2-induced immune potencies, suggesting that IL-28B could be used as a molecular adjuvant to optimize the design of E2 subunit vaccine for more effective controls of the CSF disease.

关键词： Brazilian population   HLA-DPB1   new allele   NGS   REDOME  

摘要： Identification of three novel HLA alleles HLA-DPB1*1619:01, -DPB1*1621:01, and -DPB1*1737:01 in Brazilian individuals.

关键词： Prostaglandin E2   E -type prostanoid receptor   Crassostrea gigas   Cytokine production   Haemocytes  

摘要： Prostaglandin E2 imparts diverse physiological effects on multiple cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4), among which the EP4 is one of subtypes known to mediate the immune response in mammalian monocytes and macrophages. However, the precise characteristics and functions of EP4 in mollusks remain unclear. In the present study, an EP4 homologue (designated as CgEP4) was identified from oyster Crassostrea gigas. CgEP4 contained a seven-helix transmembrane domain, shared significant homology with its vertebrate homologs, and clustered with EP4s from other Mollusca by phylogenetic analysis. When CgEP4 was transfected and expressed in HEK293 cell line, the concentration of intracellular Ca2+ was significantly increased after treatment with its agonist PGE2, while that of cAMP was not obviously changed. The mRNA transcripts of CgEP4 were dominantly expressed in haemocytes, which was 28.37-fold (p < 0.05) higher than that in hepatopancreas. By immunofluorescence analysis, CgEP4 was found to be mainly expressed in the agranulocyte subpopulation, and CgEP4(+) agranulocyte accounted for 18 % of total haemocytes. After Vibrio splendidus stimulation, the mRNA expression of CgEP4 in haemocytes was not obviously changed at the first 12 h, then significantly up-regulated at 24 h, which was 2.7-fold (p < 0.01) of that in control group. After PGE2 treatment in vivo, the phosphorylation of JNK (p-JNK) in haemocytes, but not the phosphorylated ERK (p-ERK), was significantly decreased, which was 0.64-fold (p < 0.05) of that in control group. Simultaneously, the mRNA expression levels of CgTNF-1 and CgTNF-2 in haemocytes dramatically down-regulated, which were 0.06-fold (p < 0.05) and 0.73-fold (p < 0.05) of that in control group at 24 h. When the EP4 antagonist Grapiprant was added with PGE2 treatment in vivo, the p-JNK in haemocytes significantly increased, concomitant with the up-regulation of expressions of CgTNF-1 and CgTNF-2

关键词： brodalumab   psoriasis   obesity   interleukin-17 inhibitors   failure  

摘要： Background/Objectives: Brodalumab is a monoclonal antibody against the anti-IL-17 receptor A, approved for patients with moderate-to-severe psoriasis. This retrospective study investigated patients in clinical practice to assess the impact of body weight and previous treatments with biologics on the effectiveness of brodalumab. Methods: Patients were treated according to clinical practice, and assessed at baseline, 16, 36 and 52 weeks by means of the Psoriasis Area Severity Index (PASI) and DLQI score. Overall, 299 patients were included (147 na & iuml;ve to biologics). Results: Mean PASI was significantly reduced compared with the baseline in the overall population by week 4 and continued to decrease at each study time point (15.9 +/- 7.9 at baseline, 5.4 +/- 5.3 at week 4, 1.9 +/- 3.6 at week 6, 1.0 +/- 2.1 at week 36, and 0.8 +/- 2.1 at week 52;p < 0.001 at each control). PASI improved significantly both in bio-na & iuml;ve and bio-experienced patients (p < 0.001). The proportions of patients achieving PASI 75, PASI 90, and PASI 100 were comparable between the bio-na & iuml;ve and bio-experienced groups at all time points. The percentages of patients who achieved PASI 75 were similar in obese and non-obese subjects at all determinations except the visit performed after 36 weeks of treatment (94.3% non-obese vs. 83.1% obese, p = 0.005). PASI 90 was achieved more frequently among non-obese patients than obese patients after 36 weeks (80.7% vs. 64.4%, p = 0.008) and 52 weeks of treatment (84.1% vs. 71.7%, 0.027). The probability of achieving PASI 75 and PASI 100 was independent of nutritional status at any time during the study. Conclusions: In conclusion, our results confirm that brodalumab has both rapid and sustained effectiveness in patients with moderate-to-severe psoriasis;our results could be extended to patients with multiple risk factors impairing treatment response, such as multiple biological failure and obesity.

关键词： chronic pancreatitis   pancreatic cancer   IL-17   tumour-infiltrating lymphocytes   immune microenvironment  

摘要： Immunotherapy has made progress in the treatment of tumours;however, in patients with pancreatic cancer, immunotherapy has not achieved effective results. The present study investigated changes in the immune microenvironment during tumour development and progression, and the relationship between the immune microenvironment and prognosis, to clarify the mechanism of immune escape in pancreatic cancer. A total of 40 patients with pancreatic cancer (including 22 with stage I-II disease and 18 with stage III-IV disease) and 20 patients with chronic pancreatitis were included in the present study. The expression of CD3, CD4, CD8, CD56, IFN-gamma, IL-17 and 4-1BBL was assessed by immunohistochemistry, and the mRNA expression levels were detected by reverse transcription-quantitative PCR (RT-qPCR). The clinicopathological characteristics and prognoses of patients with pancreatic cancer were analysed to further explore the role of IL-17, IFN-gamma, 4-1BBL and tumour-infiltrating lymphocytes in pancreatic cancer. Notably, the expression levels of CD3, CD8, CD56, IFN-gamma and 4-1BBL in patients with stages I-II and III-IV cancer were lower than those in patients with chronic pancreatitis (P<0.05), especially in patients with stage III-IV cancer (P<0.05). In addition, the expression of IL-17 in patients with stages I-II and III-IV cancer was greater than in patients with chronic pancreatitis (P<0.05), especially in patients with stage III-IV cancer (P<0.05). The RT-qPCR results regarding CD3, CD4, CD8, CD56, IFN-gamma and IL-17 were almost the same as those obtained from immunohistochemical analysis;however, the mRNA expression levels of 4-1BBL were not significantly different between stages I-II and III-IV. Furthermore, patients with pancreatic cancer with higher expression levels of CD3, CD8, CD56, IFN-gamma and 4-1BBL exhibited longer survival, whereas those with higher expression of IL-17 had a shorter survival time. The expression levels of CD3, CD8, CD56, cytokines IL-1