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Aim To investigate the functions of ThGM-CSF cells in the host defense against L. monocytogenes infection. Material 168 Wild-type (WT, C57BL/6J) mice and 18 GM-CSF deficient (Csf2−/−) mice were used in this study. In vitro bone marrow-derived macrophages (BMDMs) and ThGM-CSF cells were respectively derived from bone marrow and spleen. Methods A protective immune mouse model was established with L. monocytogenes. Flow cytometry, enzyme-linked immunosorbent assay, and quantitative RT-PCR were used to detect the expression of related immune cells and proteins at cellular, protein and mRNA levels. Plate counts and immunofluorescence were used to determine bacterial colonization. Results ThGM-CSF cells contribute to the protective immune response against L. monocytogenes infection. The induction of GM-CSF is significantly increased in both primary and secondary infection. Csf2−/− mice are more susceptible to L. monocytogenes infection and transfer of ThGM-CSF cells enhanced the clearance of L. monocytogenes. Anti-GM-CSF neutralizing antibody impaired the elimination of L. monocytogenes and the generation of protective immune response. Depletion of macrophages and neutrophils decreased ThGM-CSF cells development. GM-CSF promotes phagocytosis of macrophages and neutrophils to clear L. monocytogenes. Conclusion The results suggest that ThGM-CSF cells are significantly involved in the generation of protective immune responses against bacterial infection.

(1-x)BiScO3-xPbTiO3 (BS-PT) ceramics have excellent piezoelectricity and high Curie temperature at its morphotropic phase boundary (x=0.64), so it is a promising piezoelectric material for fabricating high temperature ultrasonic transducer (HTUT). Electric properties of 0.36BS-0.64PT ceramics were characterized at different temperature, and a HTUT with the center frequency of about 15 MHz was designed by PiezoCAD based on the measuring results. The prepared HTUT was tested in a silicone oil bath at different temperature systematically. The test results show that the HTUT can maintain a stable electrical resonance until 290 °C, and get a clear echo response until 250 °C with slight changes of the center frequency. Then a stepped metal block submerged in silicone oil was imaged by the HTUT until 250 °C. Velocity of silicone oil and axial resolution of the HTUT at different temperature were calculated. The results verify the capability of 0.36BS-0.64PT based HTUT for high temperature ultrasonic imaging applications.

In order to obtain an ultrasonic transducer (UT) with ultra-broad bandwidth (BW), a multilayer stairstep piezoelectric structure (MSPS) is designed and fabricated. Based on the theoretical computation, the relationship between the resonant frequency and thickness of the piezoelectric layer is obtained. The designed MSPS includes 15 layers from center to side, and its frequency range is 5–22 MHz. The finite element method (FEM) based PZFlex software is used to predict the performance of UT with the designed MSPS, and the thickness of each layer is optimized according to the simulation results to achieve the ultra-broad-BW UT. The UT with the designed MSPS is fabricated and systematically characterized. The measured results show that the fabricated UT has a center frequency of 10.54 MHz and a −6 dB BW of 121%, which agree well with the simulation results (11.75 MHz and 140%). The MSPS has significant potential in UT applications.

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244⁻CXCR6⁻), C1 (CD244⁻CXCR6⁺), or C2 (CD244⁺CXCR6⁺) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244⁺CXCR6⁺ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells., 新規の循環型iNKT細胞を発見 --抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待--. 京都大学プレスリリース. 2022-10-24.

The performance of piezoelectric ultrasonic transducer (PUT) is obviously affected by its matching layer. An intelligent optimization method for matching layer of PUT is proposed to fabricate PUT with high performance. The original data, including matching layer and performance parameters of PUT, is obtained by PiezoCAD software. Then the neural network models are established to mathematically characterize the effect of matching layer on the performance of PUT. The optimization criteria for PUT is constructed according to its performance requirements, such as center frequency (CF), bandwidth (BW) and pulse width (PW). In order to decrease the material cost, the thicknesses of matching layers are also considered in the optimization criteria. The modified particle swarm optimization algorithm is used to optimize the thicknesses of matching layers (Ag-epoxy and Parylene C). According to the designed performance, the optimized thicknesses of Ag-epoxy and Parylene C are about $54~\mu \text{m}$ and $21~\mu \text{m}$ , respectively. Based on the optimized thicknesses of matching layers, the simulated and experimental performances of PUT well agree with the designed ones. In addition, compared to the traditional quarter-wavelength theory, the proposed method can effectively decrease the materials cost. The −6dB BW and PW of PUT fabricated according to the optimized parameters are about 68.5% and $0.123~\mu \text{s}$ , which are better than that fabricated according to the quarter-wavelength theory (about 50% and $0.147~\mu \text{s}$ ).

Vessel-on-a-chips, which can be used to study microscale fluid dynamics, tissue-level biological molecules delivery and intercellular communication under favorable three-dimensional (3D) extracellular matrix microenvironment, are increasingly gaining traction. However, not many of them can allow for long-term perfusion and easy observation of angiogenesis process. Since angiogenesis is necessary for the expansion of tumor, antiangiogenic drugs play a significant role in cancer treatment. In this study, we established an innovative and reliable antiangiogenic drug screening chip that was highly modularly integrated for long-term perfusion (up to 10 days depending on the hydrogel formula) and real-time monitoring. To maintain an unobstructed flow of cell-laden tubes for subsequent perfusion culture on the premise of excellent bioactivities, a polycaprolactone stent inspired by coronary artery stents was introduced to hold up the tubular lumen from the inside, while the perfusion chip was also elaborately designed to allow for convenient observation. After 3 days of perfusion screening, distinct differences in human umbilical vein endothelial cell sprouting were observed for a gradient of concentrations of bevacizumab, which pointed to the effectiveness and reliability of the drug screening perfusion system. Overall, a perfusion system for antiangiogenic drug screening was developed, which can not only conduct drug evaluation, but also be potentially useful in other vessel-mimicking scenarios in the area of tissue engineering, drug screening, pharmacokinetics, and regenerative medicine.

Blood–brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti–ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.

The functional blood-brain barrier (BBB) model can provide a reliable tool for better understanding BBB transport mechanisms and in vitro preclinical experimentation. However, recapitulating microenvironmental complexities and physiological functions in an accessible approach remains a major challenge. Here, a new BBB model with a high-cell spatial density and tightly connected biomimetic minitissue is presented. The minitissue, pivotal functional structure of the BBB model, is fabricated by a novel and easy-to-use liquid substrate culture (LSC) method, which allows cells to self-assemble and self-heal into macrosized, tightly connected membranous minitissue. The minitissue with uniform thickness can be easily harvested in their entirety with extracellular matrix. Attributed to the tightly connected minitissue formed by LSC, the fabricated BBB biomimetic model has 1 to 2 orders of magnitude higher transendothelial electric resistance than the commonly reported BBB model. It also better prevents the transmission of large molecular substances, recapitulating the functional features of BBB. Furthermore, the BBB biomimetic model provides feedback regarding BBB-destructive drugs, exhibits selective transmission, and shows efflux pump activity. Overall, this model can serve as an accessible tool for life science or clinical medical researchers to enhance the understanding of human BBB and expedite the development of new brain-permeable drugs.

( 1- x )BiScO

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown. Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo. Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu2(OH)PO4@PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo. Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu2(OH)PO4@PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu2(OH)PO4@PAA could provide visual guidance for PTT. Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.

Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating NEDD8 to target proteins. However, the roles of neddylation in stroke, remain elusive. Here, we report that NEDD8 conjugation increased after ischemic stroke and was abundantly present in neutrophils, whereas cullin-1, a key substrate of neddylation, was upregulated in endothelium. Inhibition of neddylation by MLN4924, inactivated cullin-RING E3 ligase (CRL), reduced brain infarction and improved functional outcomes. MLN4924 treatment induced accumulation of the CRL substrate NF1. Knockdown of NF1 abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and ICAM-1. Moreover, NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of PKCδ, MARCKS and MLC in cerebral microvessels. Our results demonstrate that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.

Thrombolysis is the only approved therapy for acute ischemic stroke, but its success is limited by secondary hemorrhage. Wang and colleagues report that infusion of tissue plasminogen activator (tPA) in a murine stroke model results in increased neutrophil extracellular trap (NET) formation. NETs disrupt the blood-brain barrier and increase brain hemorrhage that can be decreased by DNase I or inhibition of NET production. Targeting NETs could improve the safety of tPA administration for stroke., Key Points NETs contribute to cerebrovascular complications of tPA via cGAS-STING activation and type 1 interferon response in ischemic brain.Targeting NETs or cGAS improves thrombolytic therapy by blocking tPA-associated BBB breakdown and hemorrhage., Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains of tPA-treated mice. Blood–brain barrier (BBB) disruption after ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase I or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase I or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase I–mediated downregulation of the STING pathway and type 1 interferon production and blocked the antihemorrhagic effect of DNase I in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas−/− mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in the ischemic brain and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage., Visual Abstract

In order to improve the fabrication efficiency and performance of an ultrasonic transducer (UT), a particle swarm optimization (PSO) algorithm-based design method was established and combined with an electrically equivalent circuit model. The relationship between the design and performance parameters of the UT is described by an electrically equivalent circuit model. Optimality criteria were established according to the desired performance, then, the design parameters were iteratively optimized using a PSO algorithm. The Pb(ZrxTi1-x)O3 (PZT) ceramic UT was designed by the proposed method to verify its effectiveness. A center frequency of 6 MHz and a bandwidth of &minus, 6 dB (70%) were the desired performance characteristics. The optimized thicknesses of the piezoelectric and matching layers were 255 &mu, m and 102 &mu, m. The experimental results agree with those determined by the equivalent circuit model, and the center frequency and -6 dB bandwidth of the fabricated UT were 6.3 MHz and 68.25%, respectively, which verifies the effectiveness of the developed optimization design method.

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3–5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-β, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery., Following ischemic insult, neovascularization and vascular remodelling play an essential part in the repair of brain damage. Here the authors show that neutrophil extracellular traps serve a detrimental role in the regeneration process, limiting the functional recovery of the brain post injury.

Within the sentiment classification field, the convolutional neural network (CNN) and long short-term memory (LSTM) are praised for their classification and prediction performance, but their accuracy, loss rate, and time are not ideal. To this purpose, a deep learning structure combining the improved cross entropy and weight for word is proposed for solving cross-domain sentiment classification, which focuses on achieving better text sentiment classification by optimizing and improving recurrent neural network (RNN) and CNN. Firstly, we use the idea of hinge loss function (hinge loss) and the triplet loss function (triplet loss) to improve the cross entropy loss. The improved cross entropy loss function is combined with the CNN model and LSTM network which are tested in the two classification problems. Then, the LSTM binary-optimize (LSTM-BO) model and CNN binary-optimize (CNN-BO) model are proposed, which are more effective in fitting the predicted errors and preventing overfitting. Finally, considering the characteristics of the processing text of the recurrent neural network, the influence of input words for the final classification is analysed, which can obtain the importance of each word to the classification results. The experiment results show that within the same time, the proposed weight-recurrent neural network (W-RNN) model gives higher weight to words with stronger emotional tendency to reduce the loss of emotional information, which improves the accuracy of classification.

In the present study, corn bran arabinoxylan (CAX) were modified with sinapic acid (SA) by esterification to generate sinapic acid corn bran arabinoxylan esters (SA-CAX) with various substituted degrees. The structure of SA-CAX was characterized by FT-IR, NMR and UV spectroscopy. And the antioxidant activities of SA-CAX were evaluated by scavenging the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical, emulsion lipid oxidation test and the lipid peroxidant level test. Compared with CAX, SA-CAX exhibited superior antioxidant activities in vitro, which indicated that the attachment of SA to CAX could enhance antioxidant activities of CAX. Moreover, the aqueous solution behavior of CAX and SA-CAX was investigated by light scattering, scanning electron microscopy and rheological measurement. The SA-CAX could form the aggregates even at diluted solutions. The hydrophobic association led to a higher viscosity and stronger gel behavior of the SA-CAX aqueous solution than that of CAX aqueous solution.

Triboelectric nanogenerators (TENGs), particularly those with high flexibility and sophisticated geometry, have shown great application foreground in portable and wearable electronics. However, traditional fabrication approaches remain complicated and non-versatile, which are also impractical in the preparation of complex shapes and structures. Herein, a one-pot coaxial direct ink writing (DIW) 3D printing technique has been proposed to fabricate a fully flexible single-electrode TENG (FFTENG) with sophisticated shapes and 3D structures for the purpose of harvesting and utilizing biomechanical energy. This FFTENG is made up of a silicone elastomer shell as the triboelectric layer and an inner silicone/carbon black (CB) core as the flexible electrode. Various factors that affect the output electric performance, including the ratio of the inner and outer diameter of the printed fiber, CB content, loading frequency, applied contact force, specimen size, and external load resistance, are investigated in detail via the contact-separation test. The results show that a standard square FFTENG with a size of 30 × 30 mm2 can yield an open-circuit voltage (Voc), a short-circuit current (Isc) and a short-circuit transferred charge (Qsc) of as high as 60 V, 0.23 μA and 58 nC, respectively, and a maximum output peak power density of 15.59 mW m−2 at a matched resistance of 80 MΩ. More importantly, various shape-adaptable FFTENGs can be designed and tailored to meet the diverse needs of different applications, such as self-powered LED systems, self-charging power systems, LED control devices, self-powered tactile sensors, flexible self-monitoring grip exercisers, and flexible self-powered keyboards, and open up new avenues for use in multifunctional self-powered electronic systems, including biomechanical energy harvesting and utilization, self-powered sensing and human-machine interaction.

2–2 piezo-composite material (PCM) with high electromechanical coupling coefficient and low acoustic impedance is a kind of common PCMs for fabricating piezo-composite ultrasonic transducer (PCUT). The performance of PCUT is obviously influenced by the design parameters (DPs) of 2–2 PCM, such as its thickness, kerf, and slice width. Combining the finite element analysis simulation and artificial intelligence methods, an intelligent optimization design method is proposed to optimize the DPs of 2–2 PCM to fabricate high-performance 2–2 PCUT. In the proposed method, the neural network models are trained by the simulation data to build up the relationship between the DPs and the performance of PCUT. Using the optimization criteria established based on the center frequency (CF), bandwidth (BW), and peak-to-peak voltage (PV), the modified particle swarm optimization algorithm is employed to determine the DPs of 2–2 PCM. The desired CF, BW, and PV are 4 MHz, 40% and 3.2 V, and the optimized thickness, kerf and slice width of 2–2 PCM are 376 µm, 69.6 µm, and 34.4 µm, respectively. Finally, the optimized 2–2 PCUT is fabricated based on the optimized DPs, and then characterized systematically. The optimized 2–2 PCUT exhibits a CF of 4.57 MHz, a BW of 41.6%, a PV of 2.89 V, and an electromechanical coupling coefficient of 0.71. The simulation and experiment results are consistent with the designed targets, which verifies the availability of the proposed method.

In the face of the limited communication and computing capacity of UAV network in complex environment, in order to improve the operating efficiency of UAV cluster information security algorithm, this paper proposes a spatial optimization information security algorithm for Public Key Cryptography (RSA). Firstly, the UAV location and cluster space optimization algorithm (CA-PSO) is used to obtain the UAV location. Secondly, the optimal particle of UAV swarm is found through spatial optimization. Then the optimal particle is loaded with the UAV Cluster Information Security Optimization Algorithm (RSA-UAV). Finally, the UAV network simulation process is given. Through algorithm simulation and performance analysis, it is found that the positioning accuracy and convergence of the loaded information security algorithm are better after the improved algorithm space optimization.

Flexible near-field communication (NFC) devices for wearable electronics often work in the state of deformation. In this paper, the electrical properties of a flexible NFC device under different bending and twisting deformations are studied. Theoretical analysis and experimental results show that the electrical properties of the NFC device are closely related to the effective area of the NFC device. The larger the change rate of the effective area of the NFC antenna is, the more the decline of the electrical properties of the NFC device is. According to the theoretical analysis of the effective area of the NFC antenna, we can see that the smaller the area is, the stronger the ability of the device to resist deformation is, and the NFC device with axisymmetric structure has better electrical stability. The preliminary results are expected to serve as a reference for the optimization design of the flexible NFC devices in wearable electronics.

Abstract Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aβ, reductions in Aβ brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD., Blood-brain barrier breakdown and cerebrovascular dysfunction contribute to the pathology and cognitive deficits of Alzheimer’s disease. This study shows that ADAMTS13 is an important regulator of cerebrovascular integrity, and can play a role in mitigating Alzheimer-like vascular dysfunction, vascular amyloid pathology and cognitive decline.

T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7Rα activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Rα mutant mice: IL-7R–Y449F mice and IL-7R–M452L mice. IL-7R–Y449F mice showed decreased PI3K and STAT5 signals, whereas IL-7R–M452L mice showed decreased PI3K but significantly increased STAT5 signaling, owing to a competition between PI3K and STAT5 signaling through Y449 of IL-7Rα. The number of T, B, and mature innate lymphoid cells were markedly reduced in IL-7R–Y449F mice, whereas IL-7R–M452L mice showed impaired early T cell development and memory precursor effector T cell maintenance with the downregulation of transcription factor T cell factor–1. Peripheral T cell numbers increased in IL-7R–M452L mice with enhanced survival and homeostatic proliferation. Furthermore, although wild type and IL-7R–Y449F mice showed comparable Th1/Th2 differentiation, IL-7R–M452L mice exhibited impaired Th17 differentiation. We conclude that PI3K competes with STAT5 under IL-7Rα and maintains an appropriate signal balance for modulating T cell development and homeostasis. To our knowledge, this study provides a new insight into complex regulation of IL-7Rα signaling, which supports immune development and responses.

A probiotic strain Lactobacillus paracasei L9,which was isolated from human intestine, was investigated for its immunomodulatory activity in vivo. Results showed that L9 improved systemic immunity by enhancing the phagocytic activity of peritoneal macrophages, the proliferation ratio of splenocytes, the IgG level in the serum and the level of IgA in the mucosa. Further, L9induced theTh1-polarized immune response by elevating the IFN-?/IL-4 ratio in the mucosa. This effect was confirmed by the enhanced IL-12-inducing activity of macrophages after in vitro stimulation of L9. Also detected was increased expression of TLR-2mRNA in the mucosa. We predict that L9 could enhance innate immunity by activating TLR-2 in the mucosa, and enhance acquired immunity by promoting Th1 polarization through induced production of IL-12 by macrophages.

Industrial cloud service platform launched a series of industrial services based on cloud computing for middle and small-sized enterprises. These services include CAD, CAE and other software services utilized on industrial design and manufacturing. Due to integrating various application systems, an efficient authentication technology was urgent required to realize the exchange and sharing of the identity information in the platform. Based on analysis and compare of various mainstream Single Sign-On (SSO) technologies, this paper proposed an SSO solution by using Central Authentication Service (CAS) protocol. Proposed system makes it easy and convenient to deal with login authentication and gain identity information of the whole platform. In addition, proposed system significantly improves the user experience.

Lactobacillus paracasei subsp. paracasei LC01 (LC01) can tolerate intestinal stresses and has antioxidant activity. To evaluate the effect of the bacterium on human intestinal microflora, a randomized, double-blind, placebo-controlled human trial was carried out. Fifty-two healthy adult volunteers were randomized equally to two groups. One group consumed 12% (wt/vol) skimmed milk supplemented with 10(10) CFU of LC01 each day for the 4-week treatment period, and then consumed placebo in the next treatment period, separated by a 2-week washout. The other group followed the reverse order. Group-specific real-time PCR and biochemical analyses was used to determine the intestinal bacterial composition of fecal samples collected at the end of every period, and the concentration of short-chain fatty acids and ammonia. A significant inhibition in fecal Escherichia coli and increase in Lactobacillus, Bifidobacterium, and Roseburia intestinalis were observed after consumption of LC01. Acetic acid and butyric acid were significantly higher in the probiotic stage and fecal ammonia was significantly lower. The results indicated a modulation effect of LC01 on the intestinal microflora of young adults, suggesting a beneficial effect on bowel health. LC01 may have potential value as a probiotic.

Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13-/- mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13-/- mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13-/- mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery.

Objective As a potential of bioactive additives, corn bran arabinoxylan (CAX) was prominent in its probiotic benefits and immuno-enhancing activities. To improve the antioxidant ability of CAX, naturally occurring caffeic acid (CA) was covalently attached to CAX by esterification to generate caffeic acid corn bran arabinoxylan esters (CA-CAX) with various degrees of substitution (DS). Methods The structure of CA-CAX was analysed by NMR, and the DS was determined by HPLC. The antioxidant activity of CA-CAX was investigated on scavenging the 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical and autoxidazing methyl linoleate, and an aqueous linolenic acid dispersion was also used as an in vitro test system to examine the inhibition effect of CA-CAX on the lipid peroxidation level after UV exposure. The ability of CA-CAX to prevent H2O2-induced oxidative damage of cell was studied by reducing MDA levels and increasing SOD and GSH-Px activities in human hepatocarcinoma (HepG2) cell. Results The results certificated that CA was linked to CAX successfully with various DS. Compared with CAX, the antioxidant capacity of CA-CAX was improved significantly and enhanced with the increasing concentration and DS.

This paper proposes an intelligent microgrid energy management system (iEMS). It aims to develop and demonstrate an intelligent system at campus site through seamless integration of energy generation, storage and demand management facilities across the electric, thermal, and gas networks. This system will also have an enhanced information and communication technology (ICT) platform for supply and demand management as well as real-time energy market interactions. The major innovations proposed by the iEMS encompass advanced ICT tools such as forecasting, predictive modelling for harmonization of multi-energy grids and enabling real-time energy market interactions for maximizing cost savings without compromising operational effectiveness and grid stability. These innovations serve to either enhance system level energy savings or facilitate system integration by using advanced distributed database system and protocols such as IEEE 1888 for communication and control.

A significant fraction of network events (such as topology or route changes) and the resulting performance degradation stem from premeditated network management and operational tasks. This paper introduces a general class of Graceful Network State Migration (GNSM) problems, where the goal is to discover the optimal sequence of operations that progressively transition the network from its initial to a desired final state while minimizing the overall performance disruption. We investigate two specific GNSM problems: 1) Link Weight Reassignment Scheduling (LWRS) studies the optimal ordering of link weight updates to migrate from an existing to a new link weight assignment; and 2) Link Maintenance Scheduling (LMS) looks at how to schedule link deactivations and subsequent reactivations for maintenance purposes. LWRS and LMS are both combinatorial optimization problems. We use dynamic programming to find the optimal solutions when the problem size is small, and leverage ant colony optimization to get near-optimal solutions for large problem sizes. Our simulation study reveals that judiciously ordering network operations can achieve significant performance gains. Our GNSM solution framework is generic and applies to similar problems with different operational contexts, underlying network protocols or mechanisms, and performance metrics.