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Summary Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1 , a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1 -deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection. [ABSTRACT FROM AUTHOR]

Abstract: Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis. [Copyright &y& Elsevier]

Abstract: The degradations in the pMOS device due to gate oxide breakdown introduced by voltage stress were investigated experimentally. The stress-induced shifts in gate leakage and I–V characteristics were presented. A combined Verilog-A and sub-circuit model was first time introduced and employed to simulate the pMOS breakdown behaviors. The Verilog-A model can accurately simulate the power law characteristics of breakdown gate leakage current with a fractional coefficient. With the developed model, the simulated results and the measurements have good agreements. The traditional logic circuits, such as the inverter and the latch, have been investigated through Cadence simulations with the improved models. The latch suffers from the gate oxide breakdown significantly. The NULL Convention Logic (NCL) circuit has also been examined and analyzed systematically. The results showed substitute degradations due to the pMOS gate oxide breakdown. [Copyright &y& Elsevier]

Background & Aims: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis. Methods: We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1flox/flox mice). Acute pancreatitis was induced in these mice (HMGB1flox/flox mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. Results: After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1flox/flox mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1flox/flox mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor κB, degradation of inhibitor of κB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine−induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor κB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1flox/flox and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection. Conclusions: In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage. [Copyright &y& Elsevier]

A novel hydrogen generation material with a high capacity of H 2 release had been successfully prepared by ball milling both NaMgH 3 and Al powder. The performances of H 2 generation of the material and effects of metals, salts or complex hydrides on this material are explored. The action mechanism of NaMgH 3 , Bi and Li 3 AlH 6 on Al H 2 O reaction is investigated by means of XRD and calorimeter. The results show that doping only NaMgH 3 into Al powder can induce a reaction of Al NaMgH 3 composite with water to release H 2 , but its yield is only 42.9% at 298.15 K. Because of forming of a layer MgAl 2 (OH) 8 on the surface of the Al particles, it leads to Al could not constantly contact with water. The experimental result find that doped Bi can accelerate the rate of H 2 generation while doped Li 3 AlH 6 contributes to enhance the yield of H 2 . By doping simultaneously Bi and Li 3 AlH 6 , the amount of H 2 generation and the yield of Al NaMgH 3 Bi Li 3 AlH 6 increase to 1379.8 mL/g and 100% at 298.15 K, respectively. [ABSTRACT FROM AUTHOR]

Maternal personal history of childhood abuse has been found to predict child social-emotional problems; however, little is known about the intergenerational associations between maternal childhood abuse and child cognitive outcomes. This study aims at examining the intergenerational associations of maternal childhood emotional abuse and physical abuse with child executive functions among Chinese families with preschoolers, and exploring how these associations are mediated by maternal perspective-taking skills and mother-child conflict. Participants were 309 preschoolers (152 boys) aged 2–6 years and their mothers. Mothers reported on their childhood abuse histories, perspective taking, and mother-child conflict at baseline (T1). Five months later (T2), child executive functions including working memory, inhibitory control, and cognitive flexibility were assessed using five computerized tasks. After controlling for child gender and age, associations with child executive functions were found for maternal childhood emotional abuse, but not physical abuse. Specifically, severer childhood emotional abuse directly predicted lower levels of child cognitive flexibility. Furthermore, chained mediation paths were found from maternal childhood emotional abuse to lower levels of child working memory and inhibitory control through worse maternal perspective taking skills and then more mother-child conflicts. Our findings provide evidence for less optimal executive functions among preschoolers with emotionally abused mothers. Developing strategies to resolve the long-lasting impacts of maternal childhood emotional abuse may be important for reducing the risks of being unable to fully achieve the cognitive potentials of the next generation. [ABSTRACT FROM AUTHOR]

Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo . These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions. [ABSTRACT FROM AUTHOR]