Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage ...differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
A robust ionospheric model is indispensable for providing the atmospheric delay corrections for global navigation satellite system (GNSS) navigation and positioning and forecasting the space ...environment. The accuracy of ionospheric models is limited due to the simplified model structures. Complicated spatiotemporal variations in total electron content (TEC) biases between GNSS and international reference ionosphere (IRI) suggest a robust strategy to optimally combine GNSS and IRI TEC for high-precision modeling. In this paper, we propose a novel ionospheric data assimilation method, which is a local ensemble transform Kalman filter (LETKF), to construct an ionospheric model over Yunnan in southwestern China. We used the LETKF method to assimilate the ionospheric TEC extracted from GNSS observations in Yunnan into the IRI-2016 model. The experimental results indicate that the ionospheric data assimilation has a more pronounced improvement effect on the IRI empirical model during periods of geomagnetic quiet than during periods of geomagnetic disturbance. On quiet magnetic days, the skill score (SKS) of the assimilation is 0.60 and the root mean square error (RMSE) values before and after assimilation are 5.08 TECU and 2.02 TECU, respectively. The correlation coefficient after assimilation increases from 0.94 to 0.99. On magnetic storm days, the SKS of the assimilation is 0.42 and the RMSE values before and after assimilation are 5.99 TECU and 3.46 TECU, respectively. The correlation coefficient after assimilation increases from 0.98 to 0.99. The results suggest that the LETKF algorithm can be considered an effective method for ionospheric data assimilation.
Ionospheric total electron content (TEC) is important data for ionospheric morphology, and also an important parameter for ionospheric correction in Global Navigation Satellite System (GNSS) precise ...positioning, navigation, and radio science. In this study, we present a data assimilation model for regional ionosphere based on a local ensemble Kalman filter (LEnKF) with the International Reference Ionosphere 2016 (IRI-2016) model as the background, to assimilate ionospheric TEC observations from GNSS. To demonstrate the results, the TEC estimates from the Crustal Movement Observation Network of China (CMONOC), which is about 260 stations in China, are applied as observation. The assessments are performed against the TEC estimates from BeiDou Navigation Satellite System (BDS) geostationary earth orbit (GEO) and against the final products from the Center for Orbit Determination in Europe (CODE). The assimilation results are in good agreement with BDS GEO TEC and the CODE TEC on a quiet or disturbed day. The correlation coefficient after assimilation is increased by about 17% compared with that before assimilation, and the RMSE after assimilation is decreased by about 42% compared with that before assimilation. Furthermore, the assimilated method is also evaluated in the single-frequency precise point positioning (PPP). The experimental results indicate that the PPP/Assimilated method can improve the GNSS positioning accuracy more effectively in comparison to the PPP/CODE. These results reveal that the LEnKF method can be considered as a useful tool for ionospheric assimilation.
Background/Aims: Interleukin-17 (IL-17) is a major pro-inflammatory cytokine that initiates and maintains inflammation. However, the molecular mechanisms as to how IL-17 influences endothelial cells ...to promote neutrophil recruitment are not fully understood. Methods: Human endothelial cells (HMECs) were stimulated with IL-17, and investigated for proliferation, migration, and tubule formation activities. Transwell chemotaxis and adhesion assays were performed to assess neutrophil recruitment. Cytokine production was measured by Cytokine Array Chip and ELISA. Western blotting and immunofluorescent analysis were used to detect the phosphorylation and translocation of STAT3. Specific inhibitors, small interfering RNA, and phosphorylation mutants were used to confirm that IL-17 induced STAT3 activation via IL-17RA signaling. Results: Activation of HMECs with IL-17 induced STAT3 phosphorylation and nuclear translocation, which were associated with induction of GRO-α, GM-CSF and IL-8, and neutrophil recruitment. Phosphorylation of STAT3 was identified mainly at the tyrosine in position 705 (Y705), and the Y705F mutants attenuated IL-17-mediated STAT3 activation. Moreover, specific inhibitors, FLLL31, or siRNA silencing of STAT3 attenuated HMECs activation, resulting in inhibition of GRO-α, GM-CSF, IL-8 production, and neutrophil recruitment. Furthermore, phosphorylation of STAT3 was identified as downstream of IL-17RA signaling. Conclusions: IL-17 induced STAT3 activation as a necessary step in endothelial cell activation and neutrophil recruitment.
The infection with high-risk human papillomavirus is linked to cervical cancer, nevertheless, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown. Here, we ...knocked down endogenous E6/E7 in HPV16-positive CaSki cell lines, screened differences in miRNA expression profile with control using miRNA array. 38 miRNAs were down-regulated and 6 miRNAs were up-regulated in the E6/E7 silenced CaSki cells (>2-fold changes with P <0.05). The levels of miR-27b, miR-20a, miR-24, miR-93, and miR-106b were verified by qPCR in E6/E7 silenced CaSki and SiHa cells. MiR-27b, up-regulated by E7, promoted CaSki and SiHa cell proliferation and invasion, inhibit paclitaxel-induced apoptosis. Dual-luciferase experiment confirmed miR-27b down-regulated its target gene PLK2 through the "seed regions". The tumor suppressor PLK2 inhibited SiHa cell proliferation, reduced cell viability, and promoted paclitaxel/cisplatin -induced apoptosis. Furthermore, DGCR8 was found to mediate the up-regulation of miR-27b by HPV16 E7. Our study demonstrated that HPV16 E7 could increase DGCR8 to promote the generation of miR-27b, which accelerated cell proliferation and inhibited paclitaxel-induced cell apoptosis through down-regulating PLK2. These findings provide an insight into the interaction network of viral oncogene, miR-27b and PLK2, and support the potential strategies using antisense nucleic acid of miR-27b for therapy of cervical cancer in the future.
Virus-related diseases are seriously threatening human health, but there are currently only 10 viruses with clinically approved antiviral drugs available. As non-cellular organisms, viruses ...parasitize in living cells and rely on the protein synthesis mechanism of the host cells. In this study, we found that the antipsychotic drug trifluoperazine (TFP), a dual dopamine receptor D2 (DRD2)/calmodulin (CALM) antagonist, increases the phosphorylation of eukaryotic initiation factor 2α (eIF2α), a key factor in the regulation of protein synthesis and significantly inhibits vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) replication. CALM but not DRD2 is involved in the antiviral activity of TFP. By knockdown of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) we found that the antiviral function of TFP is dependent on PERK, a stress response kinase that mediates eIF2α phosphorylation. Furthermore, the results of animal experiments showed that TFP protects mice from lethal VSV attacks, improving the survival rate and reducing lung injury. Taken together, these data suggests that TFP inhibits virus replication through PERK-eIF2α axis, and this broad-spectrum of mechanisms are worth further evaluation in clinical trials in the future.
The mechanisms by which vitamins regulate immunity and their effect as an adjuvant treatment for tuberculosis have gradually become very important research topics. Studies have found that vitamin B5 ...(VB5) can promote epithelial cells to express inflammatory cytokines. We aimed to examine the proinflammatory and antibacterial effect of VB5 in macrophages infected with
(MTB) strain H37Rv and the therapeutic potential of VB5
with tuberculosis. We investigated the activation of inflammatory signal molecules (NF-κB, AKT, JNK, ERK, and p38), the expression of two primary inflammatory cytokines (tumor necrosis factor and interleukin-6) and the bacterial burdens in H37Rv-infected macrophages stimulated with VB5 to explore the effect of VB5 on the inflammatory and antibacterial responses of macrophages. We further treated the H37Rv-infected mice with VB5 to explore VB5's promotion of the clearance of H37Rv in the lungs and the effect of VB5 on regulating the percentage of inflammatory cells. Our data showed that VB5 enhanced the phagocytosis and inflammatory response in macrophages infected with H37Rv. Oral administration of VB5 decreased the number of colony-forming units of H37Rv in lungs of mice at 1, 2, and 4 weeks after infection. In addition, VB5 regulated the percentage of macrophages and promoted CD4
T cells to express interferon-γ and interleukin-17; however, it had no effect on the percentage of polymorphonuclear neutrophils, CD4
and CD8
T cells. In conclusion, VB5 significantly inhibits the growth of MTB by regulating innate immunity and adaptive immunity.
Population genetic structure is strongly affected by dispersal events, especially for migratory species. The investigation of population structure is therefore conducive to increasing our ...understanding of species dispersal.
(Fabricius) (Lepidoptera: Noctuidae) is an important tobacco pest in China causing serious damage to multiple crops. In this study, we explore its dispersal dynamics by clarifying the fine-scale population genetics using 545
samples collected from tobacco plantations at 24 locations (mainly in Baise, Hechi, and Hezhou, Southern China). We analyzed the genetic diversity, genetic structure, and gene flow of these populations using seven microsatellite loci. Our results revealed high genetic diversity and low population genetic structure among
. The genetic distance was uncorrelated with geographical distance, indicating the complete randomness of dispersal among the local populations. Our results suggest that the movement scope of contemporary
might be much higher than the local-level spatial scale, which will provide a theoretical basis for pest management.
T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody ...production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part
promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity
neighboring GC-Tfh cells.
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