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The spatiotemporal distribution of cloud-to-ground (CG) lightning activities on the Yungui Plateau is investigated in this study by using a 5-year dataset (2016–2020) from the ground-based National Lightning Detection Network (CNLDN). The correlations between the lightning activities and different meteorological factors in the region are also analyzed. The results show that there is an obvious difference in the spatial distribution of lightning activities on the Yungui Plateau during the 5 years, with high lightning density in the east and low lightning density in the west. The lightning activities shift and gather more towards the eastern plateau especially after 2019. Affected by the quasi-stationary front in Kunming, the spatial distributions of lightning flashes in cold and warm seasons are different. On the other hand, the frequency of the lightning activities varies from year to year, such as the surge in 2019. But in general, 62% of the lightning activities are produced in summer and the lightning flashes occur more often in the afternoon and evening on the Yungui Plateau. Additionally, it is found that lightning activities in the 5 years are closely related to precipitation and temperature, while there is a weak correlation with relative humidity and almost no correlation with sensible heat flux. The analysis also indicates that the CAPE×P (convective available potential energy times precipitation rate) proxy can be effectively used to describe and predict lightning activities on the Yungui Plateau as the lightning flashes corresponds well to CAPE×P, especially of the spatial distribution.

Although γδ-T cell-based tumor immunotherapy using phosphoantigens to boost γδ-T cell immunity has shown success in some cancer patients, the clinical application is limited due to the rapid exhaustion of Vγ9Vδ2-T cells caused by repetitive stimulation from phosphoantigens and the profoundly immunosuppressive tumor microenvironment (TME). In this study, using a cell culture medium containing human and viral interleukin-10 (hIL-10 and vIL-10) secreted from EBV-transformed lymphoblastoid B cell lines (EBV-LCL) to mimic the immunosuppressive TEM, we found that the antitumor activity of Vγ9Vδ2-T cells was highly suppressed by endogenous hIL-10 and vIL-10 within the TME. CD137 costimulation could provide an anti-exhaustion signal to mitigate the suppressive effects of IL-10 in TME by suppressing IL-10R1 expression on Vγ9Vδ2-T cells. CD137 costimulation also improved the compromised antitumor activity of Vγ9Vδ2-T cells in TME with high levels of IL-10 in Rag2-/- γc-/- mice. In humanized mice, CD137 costimulation boosted the therapeutic effects of aminobisphosphonate pamidronate against EBV-induced lymphoma. Our study offers a novel approach to overcoming the obstacle of the hIL-10 and vIL-10-mediated immunosuppressive microenvironment by costimulating CD137 and enhancing the efficacy of γδ-T cell-based tumor therapy.

This study is performed to analyze the effects of both soil water content and porosity, two of the influencing factors of the finite conductivity, on the propagation of lightning electromagnetic fields (LEMFs) and lightning-induced voltages (LIVs) on overhead lines. A two-dimensional finite difference time domain (FDTD) model together with an improved Archie’s soil model is adopted for the field calculation at close distances from the lightning channel. The obtained results confirm that the soil water content and porosity have notable impacts on the peak values of LEMFs, especially the horizontal electric field. Moreover, the soil water content and porosity are correlated when acting together. The peak values of the horizontal electric field are found to be markedly influenced by the porosity changes at high water content or the water content changes at low porosity. The LIVs on overhead lines in these two cases are also studied. There appear to be greater differences in the induced voltages as the water content changes at low porosity.

Phytophthora root rot (PRR) caused by Phytophthora sojae, is one of the most destructive soybean diseases. The deployment of resistant cultivars is an important disease management strategy. To this aim, the development of a fast and effective method to evaluate soybean resistance to P. sojae is strategic. In this study, a detached-petiole inoculation technique was developed and its reliability was verified in soybean cultivars and segregant populations for PRR resistance. The detached-petiole and hypocotyl inoculation methods were used to assess the resistance of soybean cultivars, the F2 population of a Zhonghuang47×Xiu94-11 cross, and the derivedF2:3 population. The reactions of 13 analysed cultivars to three P. sojae isolates were consistent between the two inoculation techniques. The reactions of the F2 and Fv2:3 populations to isolate PsMC1 were 95.20% similar between the two inoculation methods. The segregation of the resistance and susceptibility fit a 3 : 1 ratio. Our results suggest that the detached-petiole technique is a reliable method, and reveal that the PRR resistance in Xiu94-11 is controlled by a single dominant gene. The phenotypic ratios of the tested Jikedou2×Qichadou1 F2 population using the detached-petiole inoculation technique fit a 3 : 1 ratio (Resistance : Susceptibility). This demonstrated that Qichadou1 contains a single dominant gene conferring resistance to P. sojae. Our new detached-petiole inoculation technique is effective, reliable, non-destructive to the plant, and does not require an excessive amount of seeds. It may be suitable for the largescale screening of soybean resistance to multiple P. sojae isolates. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis (AS) is a vascular disease which causes cardiovascular diseases such as stroke, heart attack and acute coronary syndrome. It is a major cause of death worldwide, especially in developed countries. In AS, the artery walls become thickened due to the accumulation and invasion of white blood cells (foam cells) and form a fibro-fatty plaque. Hence, these investigations aim to identify the potential applications of herbal compounds targeting the AMPK signalling pathway for AS therapy. Methods: In this investigation, in vitro kinase activity was determined for a set of herbal compounds present in herbal plants and herbal medicines against 5' AMP-activated protein kinase (AMPK). This enzyme plays a vital role in AS, having an effect on the invasion and accumulation of white blood cells, leading to the thickening of artery walls and vascular remodelling. In addition, a molecular docking simulation study was carried out for the AMPK enzyme (PDB ID: 3AQV) against the herbal compounds. Results: The in vitro kinase activity showed that 10 of the herbal compounds possessed IC50 values lower than 10 µM, which showed the potent inhibitory effect of the AMPK enzyme. In addition, a molecular docking simulation carried out on the AMPK enzyme (PDB ID: 3AQV) against the herbal compounds observed a positive correlation with IC50 values and docking scores of the docked compounds with an ICµ <10 µM. The subsequent protein-ligand interaction analyses for the best docking hits showed favourable interactions. Also, the molecular dynamics simulation enabled the generation of a trajectory file for the RMSD backbone, illustrating the stability of the docked protein-ligand complex without any structural fluctuations. Conclusions: The study concludes that baicalin, curcumin, campesterol, emodin and gingerol provide a promising lead for AS and can therefore be prescribed for the treatment of AS. [ABSTRACT FROM AUTHOR]

Objective To establish an analysis method for detecting 9 sweeteners including acesulfame, sodium saccharin, cyclamate, aspartame, sucralose, neotame, alitame, stevioside and steviobioside in spirits by using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Methods After the sample was heated by boiling water bath to remove ethanol, it was detected by UPLC-MS/MS. The sweeteners were separated by UPLC with water (containing 10 mmol/L ammonium acetate) -methanol gradient elution in a HSS T3 chromatography column (2.1 mm×100 mm, 1.7 μm), and qualified/quantified by mass spectrometry with electron spray ionization multiple reaction monitoring mode. Results The linearity of the 9 sweeteners in the range was good, and the correlation coefficient was above 0.999. The recovery of the method was 85.2%-102.8%, the relative standard deviation (RSD) was 3.8%-7.3%. The detection limit was 0.3-1.5 μg/kg. Conclusion The method is simple, rapid and reproducible, and can be used for the detection of 9 sweeteners in spirits.

Abstract Windows are the least energy efficient part of the buildings, as building accounts for 40% of global energy consumption. Traditional smart windows can only regulate solar transmission, while all the solar energy on the window is wasted. Here, for the first time, the authors demonstrate an energy saving and energy generation integrated smart window (ESEG smart window) in a simple way by combining louver structure solar cell, thermotropic hydrogel, and indium tin oxides (ITO) glass. The ESEG smart window can achieve excellent optical properties with ≈90% luminous transmission and ≈54% solar modulation, which endows excellent energy saving performance. The outstanding photoelectric conversion efficiency (18.24%) of silicon solar cells with louver structure gives the smart window excellent energy generation ability, which is more than 100% higher than previously reported energy generation smart window. In addition, the solar cell can provide electricity to for ITO glass to turn the transmittance of hydrogel actively, as well as the effect of antifreezing. This work offers an insight into the design and preparation together with a disruptive strategy of easy fabrication, good uniformity, and scalability, which opens a new avenue to realize energy storage, energy saving, active control, and antifreezing integration in one device.

Background Radiotherapy is the first-line treatment for patients nasopharyngeal carcinoma (NPC), but its therapeutic efficacy is poor in some patients due to radioresistance. Adoptive T cell-based immunotherapy has also shown promise to control NPC; however, its antitumor efficacy may be attenuated by an immunosuppressive tumor microenvironment. Exosomes derived from γδ-T cells (γδ-T-Exos) have potent antitumor potentials. However, it remains unknown whether γδ-T-Exos have synergistic effect with radiotherapy and preserve their antitumor activities against NPC in an immunosuppressive tumor microenvironment.Methods γδ-T-Exos were stained with fluorescent membrane dye, and their interactions with NPC were determined both in vitro and in vivo. NPC cell deaths were detected after treatment with γδ-T-Exos and/or irradiation. Moreover, effects of γδ-T-Exos on radioresistant cancer stem-like cells (CSCs) were determined. The therapeutic efficacy of combination therapy using γδ-T-Exos and irradiation on NPC tumor progression was also monitored in vivo. Finally, the tumor-killing and T cell-promoting activities of γδ-T-Exos were determined under the culture in immunosuppressive NPC supernatant.Results γδ-T-Exos effectively interacted with NPC tumor cells in vitro and in vivo. γδ-T-Exos not only killed NPC cells in vitro, which was mainly mediated by Fas/Fas ligand (FasL) and death receptor 5 (DR5)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, but also controlled NPC tumor growth and prolonged tumor-bearing mice survival in vivo. Furthermore, γδ-T-Exos selectively targeted the radioresistant CD44+/high CSCs and induced profound cell apoptosis. The combination of γδ-T-Exos with radiotherapy overcame the radioresistance of CD44+/high NPC cells and significantly improved its therapeutic efficacy against NPC in vitro and in vivo. In addition, γδ-T-Exos promoted T-cell migration into NPC tumors by upregulating CCR5 on T cells that were chemoattracted by CCR5 ligands in the NPC tumor microenvironment. Although NPC tumor cells secreted abundant tumor growth factor beta to suppress T-cell responses, γδ-T-Exos preserved their direct antitumor activities and overcame the immunosuppressive NPC microenvironment to amplify T-cell antitumor immunity.Conclusions γδ-T-Exos synergized with radiotherapy to control NPC by overcoming the radioresistance of NPC CSCs. Moreover, γδ-T-Exos preserved their tumor-killing and T cell-promoting activities in the immunosuppressive NPC microenvironment. This study provides a proof of concept for a novel and potent strategy by combining γδ-T-Exos with radiotherapy in the control of NPC.

Raw image classification datasets generally maintain a long-tailed distribution in the real world. Standard classification algorithms face a substantial issue because many labels only relate to a few categories. The model learning processes will tend toward the dominant labels under the influence of their loss functions. Existing systems typically use two stages to improve performance: pretraining on initial imbalanced datasets and fine-tuning on balanced datasets via re-sampling or logit adjustment. These have achieved promising results. However, their limited self-supervised information makes it challenging to transfer such systems to other vision tasks, such as detection and segmentation. Using large-scale contrastive visual-language pretraining, the Open AI team discovered a novel visual recognition method. We provide a simple one-stage model called the text-to-image network (TIN) for long-tailed recognition (LTR) based on the similarities between textual and visual features. The TIN has the following advantages over existing techniques: (1) Our model incorporates textual and visual semantic information. (2) This end-to-end strategy achieves good results with fewer image samples and no secondary training. (3) By using seesaw loss, we further reduce the loss gap between the head category and the tail category. These adjustments encourage large relative magnitudes between the logarithms of rare and dominant labels. TIN conducted extensive comparative experiments with a large number of advanced models on ImageNet-LT, the largest long-tailed public dataset, and achieved the state-of-the-art for a single-stage model with 72.8% at Top-1 accuracy.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13048-022-01060-7.

This study was aimed at screening differentially expressed genes (DEGs) and exploring the potential immune mechanism induced by the Bacillus Calmette-Guerin (BCG) vaccine in a humanized mouse model. Candidate DEGs between mice vaccinated with BCG or injected with PBS were identified through transcriptomics, and their biological functions, signaling pathways, and protein interaction networks were analyzed through bioinformatics. A total of 1035 DEGs were identified by transcriptomics: 398 up-regulated and 637 down-regulated. GO analysis indicated that these DEGs were significantly enriched in cell adhesion, oxygen transport, receptor complex, carbohydrate binding, serine-type endopeptidase activity, and peroxidase activity terms. KEGG analysis indicated that these DEGs were involved in the Rap1 signaling pathway, axon guidance, PI3K-Akt signaling pathway, natural killer cell mediated cytotoxicity, and cytokine-cytokine receptor interaction. Protein interaction network analysis demonstrated that the Myc, Vegfa, and Itgb3 proteins had the highest aggregation degree, aggregation coefficient, and connectivity. The BCG vaccine induced 1035 DEGs in humanized mice. Among them, the differentially expressed down-regulated genes myc and itgb3 involved in the PI3K-Akt signaling pathway may play essential roles in the immune mechanism of the BCG vaccine.

Development of smart and functional polymeric carriers, which enable controlled or timed release of a bioactive material, thereby providing a better dosing pattern and minimizing side effects, becomes a new requirement in the field of drug delivery. In the recent few decades, a great many advancements of polymer synthetic methods have led to a new generation of bioactive polymers' applications as drug controlled release carriers. In this review, we focus on the use of bioactive polymers for drug delivery system, with a particular in the utility of DNA-based nanocarriers and cell-penetrating peptides (CCPs)-based nanocarriers to provide precision control for drug targeting or stimuli responsive systems. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells (MSC) have been shown to have potent immunoregulatory effects. They are able to mitigate inflammation in many contexts of immune disorders, including autoimmune diseases and graft-versus-host disease (GVHD). Endotoxemia can induce systematic inflammation in the body. In this study, we try to investigate whether MSC can attenuate inflammation in models of LPS-induced endotoxemia. METHODS: Bone marrow MSC (BMSC) were isolated and expanded from rats of 4~6-week age. Adult mice were divided randomly into Control group, Model group and BMSC group. LPS were injected peritoneally into mice of Model group and BMSC group to induce endotoxemia. For BMSC group mice, 1 x 106 BMSC were injected through tail vein 1 hour after LPS application. Animals were sacrificed after 24 hours. Inflammatory damage in lungs and livers were detected through histochemistry. Wet/dry ratio of lung tissues was calculated, levels of inflammatory factors as IL-1β and TNF-α in lung tissues were measured through ELISA. RESULTS: Inflammatory pathological changes in lung and liver in BMSC group were comparable to those in Model group. Moreover, in some animals, the injuries were exacerbated after BMSC treatment. Accordingly, wet/dry ratio of lung in BMSC group mice was higher than that in Model group mice. IL-1β level in BMSC-treated group mice was significantly augmented, however, no significant changes were detected between these two groups for level of TNF-α. CONCLUSION: Our results showed that application of BMSC in LPS-induced endotoxemia models couldn't attenuate the inflammatory injuries in tissues. Although BMSC have been shown to be able to induce immune inhibition, however, in some instances, their immuno-inhibitory function might be regulated by the local environment. [ABSTRACT FROM AUTHOR]

As CNNs are widely used in fields such as image classification and target detection, the total number of parameters and computation of the models is gradually increasing. In addition, the requirements on hardware resources and power consumption for deploying CNNs are becoming higher and higher, leading to CNN models being restricted to certain specific platforms for miniaturization and practicality. Therefore, this paper proposes a convolutional-neural-network-processor design with an FPGA-based resource-multiplexing architecture, aiming to reduce the consumption of hardware resources and power consumption of CNNs. First, this paper takes a handwritten-digit-recognition CNN as an example of a CNN design based on a resource-multiplexing architecture, and the prediction accuracy of the CNN can reach 97.3 percent by training and testing with Mnist dataset. Then, the CNN is deployed on FPGA using the hardware description language Verilog, and the design is optimized by resource multiplexing and parallel processing. Finally, the total power consumption of the system is 1.03 W and the power consumption of the CNN module is 0.03 W under the premise of guaranteeing the prediction accuracy, and the prediction of a picture is about 68,139 clock cycles, which is 340.7 us under a 200 MHz clock. The experimental results have obvious advantages in terms of resources and power consumption compared with those reported in related articles in recent years, and the design proposed in this paper.

[Objective] In this study, the aim was to explore the annual dosage and allocation proportion of nitrogenous fertilizer for Zhoumai 22 in the condition of wheat-maize integration. [Method] The rules of growth and yield variation of Zhoumai 22 under different dosages of nitrogenous fertilizer and different distribution ratios were studied. [Result] With the increase of nitrogenous fertilizer application and distribution rate from maize to wheat, the physiological indexes of Zhoumai 22 population showed an increasing trend, while the yield presented the variation trend of increasing firstly and decreasing then. [Conclusion] Annual amount of nitrogenous fertilizer of 600 kg/hm2 and the distribution ratio of 5:5 in the condition of wheat-maize integration was beneficial to the high yield of the whole year's crops and Zhoumai 22. [ABSTRACT FROM AUTHOR]

Microsclerotia (MS) production by two isolates of Lecanicillium lecanii on various culture media is described, and the efficacy of MS against western flower thrips is evaluated. High concentrations of MS (2.9-3.1 x 105 mL-1 ) were produced in media with C:N ratios of 7.4:1 and 10.3:1 by isolate SN21. Bioassays using soil-incorporated MS resulted in significant infection and mortality of thrips. [ABSTRACT FROM AUTHOR]

Abstract: The solution-mined caverns have high pressure which is in proportion to the depth and specific density of brine. The cavern pressure will be approximately 12MPa at the point of 1000m below ground level. This would provide the best protection for the cavern roof and the pillar zone. Additionally, with the salt rock dissolved, the insluble mine collapsed and deposited at the bottom of cavern as loosed state around the piller zone which is also helpful to the stability of the piller. Obviously, there are essential differences between the solid-mined and the solution-mined caverns, where the simple experience in analysising the subsidence for the solid-mined caverns is poorly suited for the salt caverns. This paper focuses on the conflicts between the use of salt mine and the safety of building in the tourist area. The layout parameters of the well-group are optimized with a conbination of laboratory experiment and numerical simulation, which ensure the sagety of building and the reasonable utilization of salt. The study is extremely economical in terms of land area in beded salt mine in China. [Copyright &y& Elsevier]

Ten-year measurements of lightning and relative humidity from 2002 - 2011 have been analyzed in the Nanjing city, China. Statistical analysis shows the lightning density is positively correlated to relative humidity during this period. To further investigate the effect of relative humidity on electrification and lightning discharges in thunderstorms, a two-dimensional cumulus model incorporating dynamics, microphysics, and thunderstorm electrification mechanisms is used to present a sensitive study. The results show that the higher relative humidity in surface leads to more cloud droplet and stronger updraft, because of enhanced latent heat releasing from increasing condensation. Greater updraft and cloud water content primarily contribute to stronger ice crystal and graupel particles production with increasing relative humidity. A greater formation of cloud droplet, graupel and ice crystal result in increasing charge separation via non-inductive and inductive mechanism. The total lightning flashes increase as the relative humidity increase from 60 - 90%, and only tests with high relative humidity of 90% can produce negative cloud to ground (CG) flashes and positive CG flashes. In addition, the increase of relative humidity condition generally leads to a quicker and stronger convection, which results in earlier electrification and lightning discharges in thunderstorm.

We propose a birefringence variation independent fiber-optic current sensor based on polarization diversity and a real-time state of polarization measurement technique. We theoretically and experimentally demonstrate the compensation for the degradation of Faraday effect due to the variation in birefringence of the sensing fiber. In experiment, a maximally two times higher sensitivity was achieved compared with that of the conventional one. We investigated temperature dependence of proposed method and the observed maximal variation in sensitivity is as small as 6%. The proposed method exhibits good immunity to the random variation of birefringence and the real rotation angle due to the Faraday effect can be accurately detected.

Human Vγ9Vδ2-T cells recognize nonpeptidic antigens and exert effector functions against microorganisms and tumors, but little is known about their roles in humoral immune response against influenza virus infection. Herein, in the coculture of autologous human B cells, dendritic cells and/or naïve CD4 T cells, and Vγ9Vδ2-T cells, we demonstrated that Vγ9Vδ2-T cells could facilitate H9N2 influenza virus-specific IgG and IgM productions in a CD4 T cell-dependent manner. Vγ9Vδ2-T cells promoted the differentiation of CXCR5+PD1+CD4+ T follicular helper (Tfh) cells, CD19+IgD−CD38++ plasma cells (PCs), and drove B cell proliferation as well as immunoglobulin class switching. Interestingly, Vγ9Vδ2-T cells acquired Tfh-associated molecules such as CXCR5, PD1, CD40L, and ICOS during influenza virus stimulation, especially in the presence of CD4 T cells. Moreover, Vγ9Vδ2-T cells promoted CD4 T cells to secrete IL-13 and IL-21, and neutralizing IL-13 and IL-21 significantly reduced the number of CD19+IgD−CD38++ PCs. Using humanized mice, we further demonstrated that Vγ9Vδ2-T cells could synergize CD4 T cells to produce influenza virus-specific antibody. Our findings provide a greater scope for Vγ9Vδ2-T cells in adaptive immunity, especially for the Tfh development and humoral immune responses against influenza virus infection.

Blumeria graminis f. sp. tritici (Bgt) is an obligate biotrophic fungus that causes wheat powdery mildew, which is a devastating disease in wheat. However, little is known about the pathogenesis of this fungus, and differences in the pathogenesis of the same pathogen at various resistance levels in hosts have not been determined. In the present study, leaf tissues of both Pm40-expressing hexaploid wheat line L658 and its Pm40-deficient sister line L958 were harvested at 0 (without inoculation), 6, 12, 24, 48 and 72 hours post-inoculation (hpi) with Bgt race 15 and then subjected to RNA sequencing (RNA-seq). In addition, we also observed changes in fungal growth morphology at the aforementioned time points. There was a high correlation between percentage of reads mapped to the Bgt reference genome and biomass of the fungus within the leaf tissue during the growth process. The percentage of mapped reads of Bgt in compatible interactions was significantly higher (at the p

Inwardly rectifying potassium channels (Kirs) are important drug targets, with antagonists for the Kir1.1, Kir4.1, and pancreatic Kir6.2/SUR1 channels being potential drug candidates for treating hypertension, depression, and diabetes, respectively. However, few peptide toxins acting on Kirs are identified and their interacting mechanisms remain largely elusive yet. Herein, we showed that the centipede toxin SsTx-4 potently inhibited the Kir1.1, Kir4.1, and Kir6.2/SUR1 channels with nanomolar to submicromolar affinities and intensively studied the molecular bases for toxin–channel interactions using patch-clamp analysis and site-directed mutations. Other Kirs including Kir2.1 to 2.4, Kir4.2, and Kir7.1 were resistant to SsTx- 4 treatment.Moreover, SsTx-4 inhibited the inward and outward currents of Kirs with different potencies, possibly caused by a K+ “knock-off” effect, suggesting the toxin functions as an out pore blocker physically occluding the K+-conducting pathway. This conclusion was further supported by a mutation analysis showing that M137 located in the outer vestibule of the Kir6.2/ ΔC26 channel was the key residue mediating interaction with SsTx-4. On the other hand, the molecular determinants within SsTx-4 for binding these Kir channels only partially overlapped, with K13 and F44 being the common key residues. Most importantly, K11A, P15A, and Y16A mutant toxins showed improved affinity and/or selectivity toward Kir6.2, while R12A mutant toxin had increased affinity for Kir4.1. To our knowledge, SsTx-4 is the first characterized peptide toxin with Kir4.1 inhibitory activity. This study provides useful insights for engineering a Kir6.2/SUR1 channel–specific antagonist based on the SsTx-4 template molecule and may be useful in developing new antidiabetic drugs. [ABSTRACT FROM AUTHOR]

A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4(+) T cells and induced regulatory CD4(+) T cells (CD4(+) iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4(hi) Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4(hi) Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4(hi) Treg induced by allogeneic CD40-activated B cells. More importantly, CD4(hi) Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4(hi) Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4(hi) Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4(hi) Treg and uncover a novel relationship between ICOS and CTLA-4.

Although diverse functions of different toll-like receptors (TLR) on human natural regulatory T cells have been demonstrated recently, the role of TLR-related signals on human induced regulatory T cells remain elusive. Previously our group developed an ex vivo high-efficient system in generating human alloantigen-specific CD4(hi)CD25(+) regulatory T cells from naïve CD4(+)CD25(-) T cells using allogeneic CD40-activated B cells as stimulators. In this study, we investigated the role of TLR5-related signals on the generation and function of these novel CD4(hi)CD25(+) regulatory T cells. It was found that induced CD4(hi)CD25(+) regulatory T cells expressed an up-regulated level of TLR5 compared to their precursors. The blockade of TLR5 using anti-TLR5 antibodies during the co-culture decreased CD4(hi)CD25(+) regulatory T cells proliferation by induction of S phase arrest. The S phase arrest was associated with reduced ERK1/2 phosphorylation. However, TLR5 blockade did not decrease the CTLA-4, GITR and FOXP3 expressions, and the suppressive function of CD4(hi)CD25(+) regulatory T cells. In conclusion, we discovered a novel function of TLR5-related signaling in enhancing the proliferation of CD4(hi)CD25(+) regulatory T cells by promoting S phase progress but not involved in the suppressive function of human CD40-activated B cell-induced CD4(hi)CD25(+) regulatory T cells, suggesting a novel role of TLR5-related signals in the generation of induced regulatory T cells.

Intravenous immunoglobulin has long been used in treating autoimmune diseases, although mechanisms remain uncertain. Activating Fcγ receptors are receptors of IgG and reported to be essential in intravenous immunoglobulin (IVIG) therapy. Therefore, we hypothesized natural killer (NK) cells, which express abundant activating Fcγ receptors, are the potential cellular target. In experimental autoimmune encephalomyelitis (EAE), we demonstrated that IgG suppressed disease development in intact, but not in NK cell depleted mice. Adoptive transfer of IgG-treated NK cell could protect mice against EAE, and suppressed interferon γ and interleukin 17 production. The percentage of CD4(+)Foxp3(+) regulatory T cells was significantly increased. The increase of regulatory T cells was also observed in IgG-treated EAE mice but not in NK cell depleted mice. In vitro experiments confirmed that IgG-treated NK cells enhanced regulatory T cell induction from naïve CD4(+) T cells. Interestingly, cells from draining lymph nodes produced more interleukin 2 after the adoptive transfer of IgG-treated NK cells. We neutralized interleukin 2 and the induction of CD4(+)Foxp3(+) T cells by IgG-treated NK cells was significantly reduced. To our knowledge, we identified for the first time the critical role of NK cells in the mechanism of IgG-induced induction of Treg cells in treatment of autoimmunity.

In this study, we asked whether cytokines or soluble factors secreted upon the allogeneic immune response could favor generation of tolerogenic dendritic cells (DC). To answer this question, we cultured monocytes either in the presence of leukocyte reaction (SN-alloMLR), ii) or from HLA-identical leukocyte reaction (HLA-idMLR), or iii) GM-CSF/IL-4, as positive control. Our results showed that SN-alloMLR resulted in the differentiation of cells expressing high levels of CD54, CD40, and HLA-DR molecules but moderate levels of CD14, CD80, CD86. These cells were much more differentiated towards DC than HLA-idMLR-cultured cells. After exposure to TNF alpha for another 2 days, SN-alloMLR-cultured DC did not express the DC maturation marker CD83, neither nor an increase in CD86, as opposed with GM-CSF/IL-4-cultured DC. At the functional level, SN-alloMLR-cultured DC were not able to endocytose dextran-FITC, and secreted only low levels of IL-12, as compared with cytokine-cultured DC. Moreover, SN-alloMLR-cultured cells were unable to stimulate an alloresponse, and led to differentiation of T cells secreting high levels of IL-10, upon secondary stimulation. Altogether, these results suggest that the allogeneic immune response may induce generation of intermediate DCs, which are able to activate IL-10+ secreting T cells. [ABSTRACT FROM AUTHOR]