SUMMARY The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism.

Endogenous hydrogen sulfide (H(2)S) is naturally synthesized in various types of mammalian cells from l-cysteine in a reaction catalyzed by two enzymes, cystathionine-gamma-lyase (CSE) and/or cystathionine-beta-synthase. The latest studies have implied that H(2)S functions as a vasodilator and neurotransmitter. However, so far there is little information about the role played by H(2)S in systemic inflammation such as sepsis. Thus the aim of this study was to investigate the potential role of endogenous H(2)S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP-induced sepsis and treated with saline (ip), dl-propargylglycine (PAG, 50 mg/kg ip), a CSE inhibitor, or sodium hydrosulfide (NaHS; 10 mg/kg ip). PAG was administered either 1 h before or 1 h after the induction of sepsis, whereas NaHS was given at the same time of CLP. CLP-induced sepsis significantly increased the plasma H(2)S level and the liver H(2)S synthesis 8 h after CLP compared with sham operation. Induction of sepsis also resulted in a significant upregulation of CSE mRNA in liver. On the other hand, prophylactic as well as therapeutic administration of PAG significantly reduced sepsis-associated systemic inflammation, as evidenced by myeloperoxidase activity and histological changes in lung and liver, and attenuated the mortality of CLP-induced sepsis. Injection of NaHS significantly aggravated sepsis-associated systemic inflammation. Therefore, the effect of inhibition of H(2)S formation and administration of NaHS suggests that H(2)S plays a proinflammatory role in regulating the severity of sepsis and associated organ injury.

Hydrogen sulfide (H2S) is now considered an endogenous, gaseous mediator, which has been demonstrated to be involved in many inflammatory states. However, the mechanism of its proinflammatory function remains unknown. In the present study, we used IFN-gamma-primed human monocytic cell line U937 to investigate the effects of H2S in vitro on monocytes. We found that treatment with the H2S donor, sodium hydrosulfide, led to significant increases in the mRNA expression and protein production of TNF-alpha, IL-1beta, and IL-6 in U937 cells. H2S-triggered monocyte activation was confirmed further by the up-regulation of CD11b expression on the cell surface. We also observed that H2S could induce a rapid degradation of IkappaBalpha and subsequent activation of NF-kappaB p65, and this effect was attenuated by Bay 11-7082, a specific inhibitor of NF-kappaB. Furthermore, pretreatment of cells with Bay 11-7082 substantially inhibited the secretion of TNF-alpha, IL-1beta, and IL-6 induced by H2S. We also found that H2S stimulated the phosphorylation and activation of ERK1/2, but not of p38 MAPK and JNK, and pretreatment with PD98059, a selective MEK1 antagonist, could inhibit H2S-induced NF-kappaB activation markedly. Together, our findings suggest for the first time that H2S stimulates the activation of human monocytes with the generation of proinflammatory cytokines, and this response is, at least partially, through the ERK-NF-kappaB signaling pathway.

Zhang H, Zhi L, Moochhala S, Moore PK, Bhatia M. Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-B.

In this paper, a fuzzy adaptive approach for stochastic strict-feedback nonlinear systems with quantized input signal is developed. Compared with the existing research on quantized input problem, the existing works focus on quantized stabilization, while this paper considers the quantized tracking problem, which recovers stabilization as a special case. In addition, uncertain nonlinearity and the unknown stochastic disturbances are simultaneously considered in the quantized feedback control systems. By putting forward a new nonlinear decomposition of the quantized input, the relationship between the control signal and the quantized signal is established, as a result, the major technique difficulty arising from the piece-wise quantized input is overcome. Based on fuzzy logic systems' universal approximation capability, a novel fuzzy adaptive tracking controller is constructed via backstepping technique. The proposed controller guarantees that the tracking error converges to a neighborhood of the origin in the sense of probability and all the signals in the closed-loop system remain bounded in probability. Finally, an example illustrates the effectiveness of the proposed control approach.

Non-technical summaryOur ability to respond to stress is critically dependent upon the release of the stress hormone adrenocorticotrophic hormone (ACTH) from corticotroph cells of the anterior pituitary gland. ACTH release is controlled by the electrical properties of corticotrophs that are determined by the movement of ions through channel pores in the plasma membrane. We show that a calcium-activated potassium ion channel called SK4 is expressed in corticotrophs and regulates ACTH release. We provide evidence of how SK4 channels control corticotroph function, which is essential for understanding homeostasis and for treating stress-related disorders.AbstractThe anterior pituitary corticotroph is a major control point for the regulation of the hypothalamic–pituitary–adrenal (HPA) axis and the neuroendocrine response to stress. Although corticotrophs are known to be electrically excitable, ion channels controlling the electrical properties of corticotrophs are poorly understood. Here, we exploited a lentiviral transduction system to allow the unequivocal identification of live murine corticotrophs in culture. We demonstrate that corticotrophs display highly heterogeneous spontaneous action-potential firing patterns and their resting membrane potential is modulated by a background sodium conductance. Physiological concentrations of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) cause a depolarization of corticotrophs, leading to a sustained increase in action potential firing. A major component of the outward potassium conductance was mediated via intermediate conductance calcium-activated (SK4) potassium channels. Inhibition of SK4 channels with TRAM-34 resulted in an increase in corticotroph excitability and exaggerated CRH/AVP-stimulated ACTH secretion in vitro. In accordance with a physiological role for SK4 channels in vivo, restraint stress-induced plasma ACTH and corticosterone concentrations were significantly enhanced in gene-targeted mice lacking SK4 channels (Kcnn4−/−). In addition, Kcnn4−/− mutant mice displayed enhanced hypothalamic c-fos and nur77 mRNA expression following restraint, suggesting increased neuronal activation. Thus, stress hyperresponsiveness observed in Kcnn4−/− mice results from enhanced secretagogue-induced ACTH output from anterior pituitary corticotrophs and may also involve increased hypothalamic drive, thereby suggesting an important role for SK4 channels in HPA axis function.

No abstract

In this study, a novel adaptive neural network (NN)-based leader-following consensus approach is proposed for a class of non-linear second-order multi-agent systems. For the existing NN consensus approaches, to obtain the desired approximation accuracy, the NN-based adaptive consensus algorithms require the number of NN nodes to must be large enough, and thus the online computation burden often are very heavy. However, the proposed adaptive consensus scheme can greatly reduce the online computation burden, because the adaptive adjusting parameters are designed in scalar form, which is the norm of the estimation of the optimal NN weight matrix. According to Lyapunov stability theory, the proposed approach can guarantee the leader-following consensus behaviour of non-linear second-order multi-agent systems to be obtained. Finally, a numerical simulation and a multi-manipulator simulation are carried out to further demonstrate the effectiveness of the proposed consensus approach. IntroductionIn recent years, the consensus controls of multi-agent systems have become an active and attractive research topic because of their widespread application in various areas, such as formation control [1], sensor network [2], flocking and swarming [3] and cooperative unmanned aerial vehicles [4]. The consensus control is originally inspired from the cluster behaviour of animals, for examples, the flocking of birds [5], schooling of fish [6] and foraging of insects [7]. Usually, consensus control has two control strategies [8][9][10][11], the leaderless and the leader-following consensus. The leaderless consensus means all agents eventually arrive an agreement at a common value by a control protocol, while the leader-following consensus implies a virtual leader as a specific aim to be followed by all agents. However, most of the existing control methods, no matter leaderless or leader-following consensus, are focused on the first-order multi-agent systems. In past decades, the second-order multi-agent systems received considerable attention because of their widespread applications in practical engineering. Unlike the first-order consensus, which just needs to achieve the agreement for the only variable, the second-order consensus protocol needs to guarantee the convergence for two information states, where one is the position state and the other is the velocity state. So the second-order agreement is more challenging, and can be more widely applied to real systems. In recent decades, many eminent research results about linear second-order consensus control have been published [12][13][14][15][16][17], where [12,13] for leaderless consensus and [14-17] for leader-following consensus.In reality, most multi-agent system dynamics contain the intrinsic non-linearity. Owing to the complexity of the non-linearity, the existing linear consensus methods, such as [12][13][14][15][16][17], cannot be directly applied to non-linear systems. In recent years, several scholars have addressed the non-linear consensus problem [18][19][20][21]. In [1...