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High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3 −/− mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function.

Due to the high specific surface area, abundant nitrogen and micropores, ZIF-8 is a commonly used precursor for preparing high performance Fe-N-C catalysts. However, the Zn element is inevitably remained in the prepared Fe-N-C catalyst. Whether the residual Zn element affects the catalytic activity and active site center of the Fe-N-C catalyst caused widespread curiosity, but has not been studied yet. Herein, we built several Fe, Zn, and N co-doped graphene models to investigate the effect of Zn atoms on the electrocatalytic performance of Fe-N-C catalysts by using density functional theory method. The calculation results show that all the calculated Fe-Zn-N x structures are thermodynamically stable due to the negative formation energies and relative stabilities. The active sites around Fe and Zn atoms in the structure of Fe-Zn-N 6 (III) show the lowest oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) overpotentials of 0.38 and 0.43 V, respectively. The bridge site of Fe-Zn in Fe-Zn-N 5 shows the lowest η HER of −0.26 V. A few structures with a better activity than that of FeN 4 or ZnN 4 are attributed to the synergistic effects between Fe and Zn atoms. The calculated ORR reaction pathways on Fe-Zn-N 6 (III) show that H 2 O is the final product and the ORR mechanism on the catalyst would be a four-electron process, and the existence of Zn element in the Fe-N-C catalysts plays a key role in reducing the ORR activation energy barrier. The results are helpful for the deep understand of high-performance Fe-N-C catalysts.

Metal–organic frameworks (MOFs) are promising candidates for room‐temperature hydrogen storage materials after modification, thanks to their ability to chemisorb hydrogen. However, the hydrogen adsorption strength of these modified MOFs remains insufficient to meet the capacity and safety requirements of hydrogen storage systems. To address this challenge, a highly defective framework material known as de‐MgMOF is prepared by gently annealing Mg‐MOF‐74. This material retains some of the crystal properties of the original Mg‐MOF‐74 and exhibits exceptional hydrogen storage capacity at above‐ambient temperatures. The MgO5 knots around linker vacancies in de‐MgMOF can adsorb a significant amount of dissociated and nondissociated hydrogen, with adsorption enthalpies ranging from −22.7 to −43.6 kJ mol−1, indicating a strong chemisorption interaction. By leveraging a spillover catalyst of Pt, the material achieves a reversible hydrogen storage capacity of 2.55 wt.% at 160 °C and 81 bar. Additionally, this material offers rapid hydrogen uptake/release, stable cycling, and convenient storage capabilities. A comprehensive techno‐economic analysis demonstrates that this material outperforms many other hydrogen storage materials at the system level for on‐board applications. A novel, highly defective Mg‐MOF‐74 is reported, featuring linker vacancies that enhance hydrogen chemisorption strength at neighboring MgO5 nodes. Consequently, defective metal‐organic framework (MOF) demonstrates the capacity to absorb significant amounts of dissociated and undissociated hydrogen at temperatures up to 160 °C. This approach is anticipated to expedite the utilization of MOFs in hydrogen storage applications.

Sirtuin 6 (SIRT6), a member of the sirtuin family, is a nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase that is involved in various physiological and pathological processes. SIRT6 is generally downregulated and linked to tumorigenesis in non-small cell lung carcinoma (NSCLC), thus regarded as a promising therapeutic target of NSCLC. In this study, we investigated whether MDL-800, an allosteric activator of SIRT6, exerted antiproliferation effect against NSCLC cells in vitro and in vivo. We showed that MDL-800 increased SIRT6 deacetylase activity with an EC 50 value of 11.0 ± 0.3 μM; MDL-800 (10–50 μM) induced dose-dependent deacetylation of histone H3 in 12 NSCLC cell lines. Treatment with MDL-800 dose dependently inhibited the proliferation of 12 NSCLC cell lines with IC 50 values ranging from 21.5 to 34.5 μM. The antiproliferation effect of MDL-800 was significantly diminished by SIRT6 knockout. Treatment with MDL-800 induced remarkable cell cycle arrest at the G 0 /G 1 phase in NSCLC HCC827 and PC9 cells. Furthermore, MDL-800 (25, 50 μM) enhanced the antiproliferation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in osimertinib-resistant HCC827 and PC9 cells as well as in patient-derived primary tumor cells, and suppressed mitogen-activated protein kinase (MAPK) pathway. In HCC827 cell-derived xenograft nude mice, intraperitoneal administration of MDL-800 (80 mg · kg −1  · d −1 , for 14 days) markedly suppressed the tumor growth, accompanied by enhanced SIRT6-dependent histone H3 deacetylation and decreased p-MEK and p-ERK in tumor tissues. Our results provide the pharmacological evidence for future clinical investigation of MDL-800 as a promising lead compound for NSCLC treatment alone or in combination with EGFR-TKIs.

Binarized Neural Network (BNN) is a quantized Convolutional Neural Network (CNN), reducing the precision of network parameters for a much smaller model size. In BNNs, the Batch Normalisation (BN) layer is essential. When running BN on edge devices, floating point instructions take up a significant number of cycles to perform. This work leverages the fixed nature of a model during inference, to reduce the full-precision memory footprint by half. This was achieved by pre-computing the BN parameters prior to quantization. The proposed BNN was validated through modeling the network on the MNIST dataset. Compared to the traditional method of computation, the proposed BNN reduced the memory utilization by 63% at 860-bytes without any significant impact on accuracy. By pre-computing portions of the BN layer, the number of cycles required to compute is reduced to two cycles on an edge device.

Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis. STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.

Neonatal herpes simplex virus type 1 (HSV-1) infections contribute to various neurodevelopmental disabilities and the subsequent long-term neurological sequelae into the adulthood. However, further understanding of fetal brain development and the potential neuropathological effects of the HSV-1 infection are hampered by the limitations of existing neurodevelopmental models due to the dramatic differences between humans and other mammalians. Here we generated in vitro neurodevelopmental disorder models including human induced pluripotent stem cell (hiPSC)-based monolayer neuronal differentiation, three-dimensional (3D) neuroepithelial bud, and 3D cerebral organoid to study fetal brain development and the potential neuropathological effects induced by the HSV-1 infections. Our results revealed that the HSV-1-infected neural stem cells (NSCs) exhibited impaired neural differentiation. HSV-1 infection led to dysregulated neurogenesis in the fetal neurodevelopment. The HSV-1-infected brain organoids modelled the pathological features of the neurodevelopmental disorders in the human fetal brain, including the impaired neuronal differentiation, and the dysregulated cortical layer and brain regionalization. Furthermore, the 3D cerebral organoid model showed that HSV-1 infection promoted the abnormal microglial activation, accompanied by the induction of inflammatory factors, such as TNF-α, IL-6, IL-10, and IL-4. Overall, our in vitro neurodevelopmental disorder models reconstituted the neuropathological features associated with HSV-1 infection in human fetal brain development, providing the causal relationships that link HSV biology with the neurodevelopmental disorder pathogen hypothesis.

On the basic of the fact that all signals in the practical system are always bounded, this paper proposes a 4-degree-of-freedom (DoF) anti-windup scheme for saturated systems with parametric uncertainty. A fairly straightforward tuning rule is introduced to the robust stability analysis for the proposed anti-windup structure under the framework of IQC (Integral Quadratic Constraint). And the sufficient stability conditions are derived to check the reasonable definiteness of the related transfer function. Moreover, the control design for disturbance response and set-point tracking response are two separate part in this proposed scheme. Numerical example demonstrates the effectiveness and the considerable performance improvement of the anti-windup compensator that is designed by the proposed technique.