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To address the problem of low trigger accuracy during trigger resampling and variable sampling rate trigger resampling using a fixed sampling rate analog-to-digital converter (ADC), this paper proposes an interpolation method combining sinc interpolation and linear interpolation to improve accuracy, based on a digital trigger. After behavior simulation verification and actual field programmable gate array (FPGA) test verification, the data collected by two 3GSps 12-bit ADCs were subjected to 8-times sinc interpolation followed by 16-times linear interpolation processing, after which the original trigger resampling accuracy was increased by 128 times and the sampling rate could be realized to vary between 100 MHz and 1 GHz. A signal–noise ratio (SNR) of 46.80 dBFS, a spurious free dynamic range (SFDR) of 45.91 dB, and an effective number of bits (ENOB) of 7.48 bits were obtained by direct trigger resampling without algorithm processing in the behavior simulation. Meanwhile, an SNR of 58.98 dBFS, an SFDR of 60.96 dB, and an ENOB of 9.42 bits were obtained by trigger resampling after algorithm processing. Due to the influence of analog link signal loss and signal interference on the development board, an SNR, SFDR and ENOB of 51.97 dBFS, 61.26 dB, and 8.32 bits, respectively, were obtained from the trigger resampling in the FPGA test. The experimental results show that the algorithm has not only improved the triggering accuracy but has also improved the SNR, SFDR, and ENOB parameters.

T helper 1 (Th1) immunity is typically viewed as a critical adaptation by vertebrates against intracellular pathogens. Identifying novel targets to enhance Th1 cell differentiation and function is increasingly important for anti-infection immunity. Here, through small-molecule screening focusing on epigenetic modifiers during the in vitro Th1 cell differentiation process, we identified that the selective histone deacetylase 6 (HDAC6) inhibitors ricolinostat and nexturastat A (Nex A) promoted Th1 cell differentiation. HDAC6-depleted mice exhibit elevation of Th1 cell differentiation, and decreased severity of Listeria monocytogenes infection. Mechanistically, HDAC6 directly deacetylated CBP-catalyzed acetylation of signal transducer and activator of transcription 4 (STAT4)-lysine (K) 667 via its enzymatic activity. Acetylation of STAT4-K667 is required for JAK2-mediated phosphorylation and activation of STAT4. Stat4supK667R/supmutant mice lost the ability to normally differentiate into Th1 cells and developed severe Listeria infection. Our study identifies acetylation of STAT4-K667 as an essential signaling event for Th1 cell differentiation and defense against intracellular pathogen infections, and highlights the therapeutic potential of HDAC6 inhibitors for controlling intracellular pathogen infections.

Background Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Islet transplantation (Tx) is poised to play an important role in the treatment of T1DM. However, whether treatment of T1DM with islet Tx can rescue dysregulated microbiota remains unclear. Methods In this study, we induced diabetic C57BL/6 mice with streptozotocin. Then treatment with either insulin administration, or homogenic or allogenic islet Tx was performed to the diabetic mice. Total DNA was isolated from fecal pellets and high-throughput 16S rRNA sequencing was used to investigate intestinal microbiota composition. Results The overall microbial diversity was comparable between control (nonstreptozotocin treated) and diabetic mice. Our results showed the ratio of the Bacteroidetes: Firmicutes between nondiabetic and diabetic mice was significant different. Treatment with islet Tx or insulin partially corrects the dysregulated bacterial composition. At the genus level, Bacteroides, Odoribacter, and Alistipes were associated with the progression and treatment efficacy of the disease, which may be used as a biomarker to predict curative effect of treatment for patients with T1DM. Conclusions Collectively, our results indicate that diabetic mice show changed microbiota composition and that treatment with insulin and islet Tx can partially correct the dysregulated microbiota.

Controversial results regarding the associations between aldose reductase (AR) genetic polymorphisms and diabetic retinopathy (DR) have been reported for many years. The present meta-analysis was performed to clarify the effects of the AR gene C(-106)T polymorphism on DR risk. The PubMed, Web of Sciences, Cochrane library, EMBASE, Chinese National Knowledge Infrastructure, and Wan Fang databases were extensively searched in Chinese to select relevant studies with an updated date of April 25, 2018. The Newcastle-Ottawa Scale (NOS) was applied to assess quality. The random-effects model was applied to calculate the pooled OR and 95% CI. This meta-analysis identified 23 studies with an average score of 7.52 for NOS analysis, including 4,313 DR cases and 5,128 diabetes mellitus (DM) control cases. In the overall analysis, a significant association between the AR gene C(-106)T polymorphism and DR susceptibility was found. In subgroups stratified by DM type and ethnicity, significantly increased risks for DR were found in DM type 1, East Asian populations, and Middle Eastern populations. Compared with DR control cases, the following associations were found: T vs. C: OR 0.91, 95% CI 0.85–0.97, I2 = 72.9%; CT + TT vs. CC: OR 0.75, 95% CI 0.68–0.81, I2 = 86.7%; and CT vs. CC: OR 0.86, 95% CI 0.78–0.94, I2 = 70.5%. The results of this meta-analysis showed a significant association between the AR gene C(-106)T polymorphism and susceptibility to DR in DM patients. DM patients with allele T and CT+TT genotype of the AR gene may have a lower risk of DR.

Background The major limitation of organ transplantation is the shortage of available organs. Xenotransplantation is considered to be an effective way to resolve the problem. Immune rejection is a major hurdle for the successful survival of pig xenografts in primate recipients. Cytokines play important roles in inflammation and many diseases including allotransplantation, however, their roles in xenotransplantation have been less well investigated. Methods We assessed the role of several cytokines in xenotransplantation using an in vitro model of human antibody-mediated complement-dependent cytotoxicity (CDC). Porcine aortic endothelial cells (PAECs) and porcine iliac endothelial cells (PIECs) were selected as target cells. The complement regulators (CD46, CD55 and CD59) and junction protein genes were assessed by real-time PCR, flow cytometry, or western-blotting assay. Flow cytometry assay was also used to evaluate C3 and C5b-9 deposition, as well as the extent of human IgM and IgG binding to PIECs. Gene silencing was used to reduce genes expression in PIECs. Gene overexpression was mediated by adenovirus or retrovirus. Results Recombinant human TNF-α increased the cytotoxicity of PAECs and PIECs in a human antibody-mediated CDC model. Unexpectedly, we found that the expression of complement regulators (CD46, CD55 and CD59) increased in PIECs exposed to human TNF-α. Human TNF-α did not modify C3 or C5b-9 deposition on PIECs. The extent of human IgM and IgG binding to PIECs was not affected by human TNF-α. Human TNF-α decreased the expression of Occludin in PIECs. Gene silencing and overexpression assay suggested that Occludin was required for human TNF-α-mediated cytotoxicity of PIECs in this model. P38 gene silencing or inhibition of P38 signaling pathway with a specific inhibitor, SB203580, inhibited the reduction of Occludin expression induced by TNF-α, and suppressed TNF-α-augmented cytotoxicity of PIECs. Conclusion Our data suggest that human TNF-α increases the cytotoxicity of porcine endothelial cells in a human antibody-mediated CDC model by downregulating P38-dependent Occludin expression. Pharmacologic blockade of TNF-α is likely to increase xenograft survival in pig-to-primate organ xenotransplantation. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0386-7) contains supplementary material, which is available to authorized users.

Necroptosis is a recently defined type of programmed cell death with the specific signaling cascade of receptor-interacting protein 1 (RIPK1) and RIPK3 complex to activate the executor MLKL. However, the pathophysiological roles of necroptosis are largely unexplored. Here, we report that fungus triggers myeloid cell necroptosis and this type of cell death contributes to host defense against the pathogen infection. Candida albicans as well as its sensor Dectin-1 activation strongly induced necroptosis in myeloid cells through the RIPK1-RIPK3-MLKL cascade. CARD9, a key adaptor in Dectin-1 signaling, was identified to bridge the RIPK1 and RIPK3 complex-mediated necroptosis pathway. RIPK1 and RIPK3 also potentiated Dectin-1-induced MLKL-independent inflammatory response. Both the MLKL-dependent and MLKL-independent pathways were required for host defense against C. albicans infection. Thus, our study demonstrates a new type of host defense system against fungal infection.

The balance between gut microbiota and host is critical for maintaining host health. Although dysregulation of the gut microbiota triggers the development of various inflammatory diseases, including colitis, the molecular mechanism of microbiota-driven colitis development is largely unknown. Here, we found that gasdermin D (GSDMD) was activated during acute colitis. In the dextran sulfate sodium (DSS)-induced colitis model, compared to wild-type mice, Gsdmd-deficient mice had less colitis severity. Mechanistically, GSDMD expression in intestinal epithelial cells (IECs), but not infiltrating immune cells, was critical for GSDMD-mediated colitis progression. Moreover, commensal Escherichia coli (E. coli) largely overgrew during colitis, and then the dysregulated commensal E. coli mediated GSDMD activation. Furthermore, the activated GSDMD promoted the release of interleukin-18 (IL-18), but not the transcript or maturation level of IL-18, which in turn mediated goblet cell loss to induce colitis development. Thus, GSDMD promotes colitis development by mediating IL-18 release, and the microbiota can mediate colitis pathogenesis through regulation of GSDMD activation. Our results provide a potential molecular mechanism by which the microbiota-driven GSDMD activation contributes to colitis pathogenesis.

Summary Cardiac hypertrophy is an adaptive response to all forms of heart disease, including hypertension, myocardial infarction, and cardiomyopathy. Cyclooxygenase-2 (COX-2) overexpression results in inflammatory response, cardiac cell apoptosis, and hypertrophy in adult heart after injury. However, immune response-mediated cardiac hypertrophy and fibrosis have not been well documented in injured neonatal heart. This study showed that cardiac hypertrophy and fibrosis are significantly attenuated in celecoxib (a selective COX-2 inhibitor)-treated P8 ICR mice after cryoinjury. Molecular and cellular profiling of immune response shows that celecoxib inhibits the production of cytokines and the expression of adhesion molecular genes, increases the recruitment of M1-like macrophage at wound site, and alleviates cardiac hypertrophy and fibrosis. Furthermore, celecoxib administration improves cardiac function at 4 weeks after injury. These results demonstrate that COX-2 inhibition promotes the recruitment of M1-like macrophages during early wound healing, which may contribute to the suppression of cardiac hypertrophy and fibrosis after injury., Graphical abstract, Highlights • Cryoinjury successfully induces cardiac hypertrophy and fibrosis in P8 ICR mice • COX-2 inhibition alleviates cardiac hypertrophy and fibrosis after cryoinjury • MCP-1 significantly increases in COX-2 inhibition • COX-2 inhibition improves cardiac repair in P8 ICR mice by recruiting M1-like macrophages, Animal Physiology; Molecular Physiology; Molecular Biology

It is a key issue of how to improve the efficiency and security in the development of oil shale, which is associated with the evolutions of permeability, pore and fracture structures of oil shale under the condition of high temperature. To investigate the influences of temperature and tri-axial stresses on the permeability of oil shale, the WYF-1 high-temperature and high-pressure pyrolysis reaction device and Smart perm III impulse-type gas permeability measuring apparatus were used to test the oil shale samples after a temperature ranging from 20 ℃ to 600 ℃. Moreover, the mercury intrusion porosimetry was also used to analyze the evolution of pore and fracture structure inside the specimen. The results show that the temperature has a significant effect on the permeability of oil shale that can be divided into three stages: low growth stage, rapid growth stage, and steady stage. At the low growth stage that the temperature is from 20 ℃ to 300 ℃, the weight loss rate and porosity change of oil shale are rare and the permeability of oil shale gradually increases with raising the temperature, and the volumetric stress (13 MPa, 26 MPa, 39 MPa) has little effect on the permeability; However, for the rapid growth stage with the temperature from 300 to 400 ℃, its weight loss and porosity increased rapidly, and the permeability increased sharply by 24.3 to 92.4 times of that at the temperature of 300 ℃, the volume stress showed an obvious effect on the permeability; Lastly, for the temperature from 400 to 600 ℃, the weight loss rate and porosity further increased but the growth rate slowed down, resulting in that the permeability nearly kept constant with temperature, and the volumetric stress has a larger influence on the permeability. Besides, the mercury intrusion porosimetry was used to investigate the distribution law and connectivity characteristics of pore and fractures. The porosity sharply increased with the temperature reaching 400 ℃ and further increased with the temperature until 600 ℃, which corresponds to the evolution of permeability of oil shale. This research can provide some guidance for the selection of a reasonable pyrolysis temperature in the process of in situ pyrolysis of oil shale.

The transplanted organs or cells survive if the recipient receives adequate long-term immunosuppressive therapy. Immunosuppressive therapy combined with cell-based strategies (eg, regulatory T cell [Treg]-based therapy) promotes graft survival. A combination of Treg-based therapy and minimal or no immunosuppressive drug therapy would have the potential to minimize the risks of the complications and side effects of these drugs. Fortunately, some immunosuppressive and other agents not only impede the effector T cell response, but also help generate new CD4+ Tregs from conventional effector T cells. These agents include IL-2, TGF-β, agents that block the CD40/CD40L costimulation pathway, mTOR inhibitors, and histone deacetylase inhibitors. Consequently, a state of relative unresponsiveness to the transplanted organ may be induced through the expansion of Tregs. We here review the effect of these various agents on expansion of CD4+ Tregs in allo- and xenotransplantation. The expansion of Tregs might allow a dose reduction of the standard immunosuppressive drugs.

Pancreatic islet transplantation is a well-established therapeutic treatment for type 1 diabetes. The kidney capsule is the most commonly used site for islet transplantation in rodent models. However, the tight kidney capsule limits the transplantation of sufficient islets in large animals and humans. The inguinal subcutaneous white adipose tissue (ISWAT), a new subcutaneous space, was found to be a potentially valuable site for islet transplantation. This site has better blood supply than other subcutaneous spaces. Moreover, the ISWAT accommodates a larger islet mass than the kidney capsule, and transplantation into it is simple. This manuscript describes the procedure of mouse islet isolation and transplantation in the ISWAT site of syngeneic diabetic mouse recipients. Using this protocol, murine pancreatic islets were isolated by standard collagenase digestion and a basement membrane matrix hydrogel was used for fixing the purified islets in the ISWAT site. The blood glucose levels of the recipient mice were monitored for more than 100 days. Islet grafts were retrieved at day 100 after transplantation for histological analysis. The protocol for islet transplantation in the ISWAT site described in this manuscript is simple and effective.

A distributed containment control problem for asynchronous discrete-time second-order multi-agent systems with switching topologies is studied in this paper, where asynchrony means that each agent only receives the state information of its neighbors at certain discrete time instants determined by its own clock that is independent of other agents. Based on a novel containment control protocol, the asynchronous system is transformed into a matrix-vector form, which implies that the asynchronous containment control problem can be converted to a convergence problem of the product of infinite time-varying nonnegative matrices whose all row sums are less than or equal to 1. Then the relations between switching communication topologies and the composite of binary relation are exploited to solve this convergence problem. Finally, we obtain a sufficient condition that all the followers can enter and keep moving in the convex hull formed by the leaders if the union of the effective communication topologies across any time intervals with some given length contains a spanning forest rooted at the leaders. Moreover, some simulation examples are presented for illustration.

In this article, we investigate the issue of containment control for a heterogeneous multi-agent system composed of stationary leaders, first-order dynamic followers and second-order dynamic followers under switching communication topologies. For the followers with different order dynamic behavior, two distributed dynamic state feedback algorithms are constructed separately for the followers driven by different dynamics. To achieve the objective of this work, we convert the heterogeneous containment control problem into a convergence problem, which is the product of time-varying non-negative matrices whose sum of each row is less than or equal to 1. With the aid of the matrix product technique and the composite binary relation, a sufficient condition can be established to analyze the convergence problem. At last, some numerical examples are presented to verify the feasibility of the theoretical findings.

This paper aims to investigate the asynchronous group consensus problem for discrete-time heterogeneous multi-agent systems under dynamically changing interaction topologies. Here the heterogeneous system is composed of hybrid dynamic agents including first-order dynamic agents and second-order dynamic agents, and asynchrony implies that each agent only detects the neighbors’ state information at certain discrete time instants determined by its own clock that is independent of the other agents’. For different kinds of agents, two asynchronous consensus protocols are proposed to realize local control strategies, respectively. With the help of nonnegative matrix theory, in particular the product properties of row-stochastic matrices from a noncompact set, a sufficient condition in terms of the interaction topologies is established to guarantee that the asynchronous group consensus problem can be solved under very relaxed conditions, i.e., the union of the effective interaction topologies across any time intervals with some given length is only required to contain a spanning tree. Numerical examples are finally provided to validate the theoretical results.

Although usp38 has recently been reported to be in a chromosome locus associated with human asthma in a GWAS study, its potential pathological role remains unknown. Chen et al. now demonstrate that usp38 is essential for asthmatic pathogenesis. USP38 is induced by TCR signaling and in turn promotes JunB stabilization to specifically regulate Th2 cell differentiation., Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HDM. Mechanistically, USP38 directly associated with JunB, deubiquitinated Lys-48–linked poly-ubiquitination of JunB, and consequently blocked TCR-induced JunB turnover. USP38 represents the first identified deubiquitinase specifically for Th2 immunity and the associated asthma., Graphical Abstract

This study involves an examination of the dynamic consensus problem for networks of double-integrator agents with aperiodic impulsive protocol and fixed topology. With respect to each agent, the control law is designed based on relative state measurements (i.e. position and velocity) between the agent and the neighbouring agents at a few discrete times. Additionally, these state measurements can include time-varying measurement delays. The theory of impulsive differential equations is used to prove that the dynamic consensus can be achieved under the condition of a graph with a spanning tree and to provide the consensus state finally reached by all agents. Furthermore, the study establishes algebraic inequalities that should be satisfied by the control gains, the bounds of impulsive interval lengths, and the upper bound of delays. Two numerical examples are illustrated to validate the main results.

In order to study the coupled effect of the temperature and pressure on pyrolysis characteristics and pore and fracture structures of oil shale, a total of 25 groups of pyrolytic reaction experiments have been conducted on 14 mm long and 7 mm in diameter cylindrical oil shale specimens under different temperature and pressure conditions ranging from 20 to 600 °C and 0.1–15 MPa. Further, both X-ray microcomputed tomography (μCT) and mercury intrusion porosimetry (MIP) have been used to comprehensively investigate the network structure, interconnectivity, and evolution of pore and fractures. The results show that the temperature significantly affects the pyrolysis characteristics of oil shale. With rising temperature, both the mass loss and the porosity increase gradually, the number and the maximum aperture of fractures also increase, and the pyrolytic degree intensifies progressively. The increase is most significant from 300 to 500 °C. The maximum mass loss ratio is 20.84%, the largest porosity is 13.52 ...

The connection between innate and adaptive immunity is best exemplified by antigen presentation. Although antigen-presenting cells (APCs) are required for antigen receptor-mediated T-cell activation, how T-cells feedback to APCs to sustain an antigen-specific immune response is not completely clear. Here we show that CD8+ T-cell (also called cytotoxic T lymphocytes, CTL) feedback activates the NLRP3 inflammasome in APCs in an antigen-dependent manner to promote IL-1β maturation. Perforin from antigen-specific CTLs is required for NLRP3 inflammasome activation in APCs. Furthermore, such activation of NLRP3 inflammasome contributes to the induction of antigen-specific antitumour immunity and pathogenesis of graft-versus-host diseases. Our study reveals a positive feedback loop between antigen-specific CTLs and APC to amplify adaptive immunity., Perforin is part of the cytotoxic effector mechanism of CD8+ T cells. Here the authors show that antigen-induced perforin release from CD8 T cells into antigen-presenting cells can activate NLRP3 inflammasome to constitute a positive feedback loop to promote anti-tumour immunity and allo-responses.

The second-order consensus problems in multi-agent systems with undirected topologies and time-invariant delays are considered in this paper. The time-delay robustness of a consensus protocol based on periodic edge-event driven control is investigated, and the studied protocol can largely reduce the communication and controller-updating costs. The relationship between time delays and event-detecting period is characterized. By Lyapunov methods, it is shown that the protocol can solve state consensus problems when the interaction topology is connected, and the system does not exhibit Zeno behavior. Finally, simulations are given to demonstrate the effectiveness of our theoretical results.

Figure S1. TNF-α did not cause PIEC death. (A) PIECs were treated with or without rhTNF-α (20 ng/ml) for 48 h, rhTNF-α (20 ng/ml) + cycloheximide (CHX, High: 10 μg/ml) or rhTNF-α (20 ng/ml) + CHX (Low: 2 μg/ml) for 2.5 h as positive controls. Lysates were analyzed by western-blotting with antibodies against Cleaved Caspase 3 and actin. (B) PIECs were treated with rhTNF-α (20 ng/ml) or medium as a negative control (NC) for 0, 24 h, 48 h, 72 h, or 96 h. The cell number was assessed with CCK8. (C) PIECs were treated with recombinant human IL-2 (20 ng/ml), IL-15 (100 ng/ml), IL-8 (100 ng/ml), IL-6 (20 ng/ml), G-CSF (100 ng/ml), G-MCSF (50 ng/ml), IFNγ (50 ng/ml), IL-4 (20 ng/ml), or medium as a negative control (NC) for 48 h. The cell number was assessed with CCK8. Data are representative of at least three independent experiments (mean ± SEM). *p

Table S1. Listing of primers and primer sequences for real-time PCR. (DOC 47 kb)

Figure S3. Loss of P38 in PIECs was mediated by P38-specific siRNA oligos. (A-B) PIECs were transfected with control siRNA oligo or with P38-specific siRNA oligos. After 48 h, total RNA was collected and the mRNA levels of P38 were measured by RT-PCR (A), and lysates were analyzed by western-blotting (right side) with antibodies against P38, or actin (B). Data are representative of at least three independent experiments (mean ± SEM). ***p

The leader-following consensus problem for high-order multi-agent systems with heterogeneous communication topologies is addressed in this paper. Here heterogeneous topologies mean that the different-order communication topologies among the agents are different. By proposing a novel protocol and exploring the product properties of infinite matrices, it is proved under some algebraic condition that the leader-following consensus can be achieved for any initial values if the leader is globally reachable in each communication topology. Finally a numerical example is given to demonstrate the reliability and effectiveness of our theoretical result.

This paper formulates and solves the asynchronous consensus tracking problem for a discrete-time second-order multi-agent system often used in some physical systems such as robot systems, aircraft systems, and satellite systems. Asynchrony means that each agent's update times, at which the agent updates its state, are determined by its clock that is independent of those of the other agents'. Here we design two asynchronous distributed control protocols, including position control protocol and velocity control protocol. Based on the properties of the product of infinite nonnegative matrices and the composite of binary relation, we derive a sufficient condition to guarantee that the states of all the followers asymptotically converge to the state of the leader. At last a numerical example is presented to demonstrate the validity of the theoretical findings.