Doping Ru on FeNi LDH/FeII/III-MOF heterogeneous core-shell structure for efficient oxygen evolution.

Noble metal-based catalysts such as RuO2 and IrO2 are widely used in the catalysis of the OER. However, because of their high price and poor stability, it is urgent to develop transition metal-based electrocatalysts with low precious metal doping as an alternative. Layered double hydroxides (LDHs) grown on 3D metal-organic frameworks (MOFs) are ideal for doping precious metals owing to abundant defects at the heterointerface, large surface area, and intrinsic oxygen evolution activity. In this study, a novel FeNi LDH/MOF heterostructure was prepared via a two-step solvothermal method using Fe-soc-MOFs as the substrate. Subsequently, Ru was introduced through a hydrothermal process. The as-synthesized Ru@FeNi LDH/MOF has an overpotential of only 242 mV at a current density of 10 mA cm-2 and can be used in continuous electrolysis for 48 h. Its unique nanocubic core-shell structure and flower-like LDHs on its surface provide a large number of active sites, which become the key to ensuring high activity and stability. With the doping of Ru, the electronic structure was adjusted and electron transfer was accelerated, further improving electrochemical activity. This study provides a new idea for developing transition metal-based catalysts with low noble metal loading.

Fe-Based Metal Organic Framework-Derived FeNiP/N-Doped Carbon Heterogeneous Core-Shell Structures for Oxygen Evolution.

It is of great significance to explore high activity, low overpotential, and outstanding durability electrocatalysts without precious metals for oxygen evolution reaction to reduce the energy consumption in the electrolysis of water to product hydrogen. Metal organic frameworks (MOFs) with periodic structure and uniform pore distribution have been widely used as precursors for the synthesis of transition metal electrocatalysts. Herein, we first synthesized nanoscale Fe-soc-MOFs with relatively high specific surface area and in situ converted it into nickel-iron double layer hydroxide/MOF (FeNi LDH/MOF) by Ni2+ etching. Finally, a nickel-iron phosphide/nitrogen-doped carbon cubic nanocage (FeNiP/NC) was obtained by calcination and phosphating. FeNiP/NC with its unique core-shell structure has an overpotential of only 240 mV at a current density of 10 mA/cm2 and can be continuously electrolyzed for 45 h. High catalytic activity of FeNiP/NC is mainly attributed to the action of Fe and Ni bimetals and the synergistic effect between FeNiP and N-doped porous carbon, which was confirmed by the calculation of density functional theory (i.e., Gibbs free energy). After a long period of electrolysis, FeNiP was converted to MOOH (M = Fe and Ni) and became the new active site. This study provides a feasible optimization strategy for the development of high-efficiency three-dimensional electrode materials without precious metals.

Prusogliptin (DBPR108) monotherapy in treatment-naïve patients with type 2 diabetes: A randomized, double-blind, active and placebo-controlled, phase 3 study.

AIM: This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period. MATERIALS AND METHODS: In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24. RESULTS: In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups. CONCLUSIONS: DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.

Optimal dose of neostigmine antagonizing cisatracurium-induced shallow neuromuscular block in elderly patients: a randomized control study.

BACKGROUND: Residual neuromuscular block after using neuromuscular blocking agents is a common and potentially harmful complication of general anesthesia. Neostigmine is a widely used antagonist, but its optimal dose for elderly patients is unclear. OBJECTIVES: To compare the optimal dosage and safety of neostigmine for reversing shallow residual block in elderly patients after cisatracurium-induced neuromuscular block. METHODS: A randomized controlled trial was conducted in 196 elderly patients undergoing non-cardiac surgery under general anesthesia with cisatracurium. Patients were assigned to receive either no neostigmine (control group) or neostigmine at 20 µg/kg, 40 µg/kg or 50 µg/kg when train-of-four (TOF) ratio reached 0.2 at the end of surgery. The primary outcome was the time to reach TOF ratio of 0.9 after administration. Secondary outcomes included TOF ratio at 10 min after administration, postoperative nausea and vomiting, postoperative cognitive impairment and post-anesthesia care unit (PACU) stay time. RESULTS: The time to reach TOF ratio of 0.9 in the 20 µg/kg, 40 µg/kg and 50 µg/kg groups was significantly shorter than the control group (H = 104.257, P < 0.01), and the time of 40 µg/kg group and 50 µg/kg group was significantly shorter than the 20 µg/kg group (P < 0.001). There was no significant difference between 40 µg/kg and 50 µg/kg groups (P = 0.249). The TOF ratio at 10 min after administration showed similar results. There were no significant differences among groups in postoperative nausea and vomiting, postoperative cognitive impairment or post-operation hospital stay. CONCLUSIONS: Timely use of neostigmine after general anesthesia in elderly patients can significantly shorten time of TOF value reaching 0.9, among which 40 µg/kg dosage may be a more optimized choice. TRIAL REGISTRATION: this study was registered on chictr.org.cn (ChiCTR2100054685, 24/12/2021).

Metal-Organic Framework Sub-Nanochannels Formed inside Solid-State Nanopore with Proton Ultra-High Selectivity.

Metal-Organic frameworks (MOFs) have the advantages of high porosity, angstrom-scale pore size, and unique structure. In this work, a kind of MOFs, UiO-66 and its derivatives (including aminated UiO-66-(NH2 )2 and sulfonated UiO-66-(NH-SAG)2 ), were constructed on the inner surface of solid-state nanopores for ultra-selective proton transport. UiO-66 and UiO-66-(NH2 )2 nanocrystal particles were in-situ grown at the orifice of glass nanopores firstly, which were used to investigate the ionic current responses in LiCl and HCl solutions when the monovalent anions (Cl- ) were unchanged. Compared with UiO-66-modifed nanopores, the aminated MOFs modification (UiO-66-(NH2 )2 ) can improve the proton selectivity obviously. However, when the UiO-66-(NH-SAG)2 nanopore is prepared by further post-modification with sulfo-acetic acid, lithium ions can hardly pass through the channel, and the interaction between protons and sulfonic acid groups can promote the transport of protons, thus achieving ultra-high selectivity to protons. This work provides a new way to achieve sub-nanochannels with high selectivity, which can widely be used in ion separation, sensing and energy conversion.

Single-Molecule Investigation of the Protein-Aptamer Interactions and Sensing Application Inside the Single Glass Nanopore.

Solid-state nanopores offer a nanoconfined space for a single-molecule sensing strategy. Evaluating the behavior of proteins and protein-related interactions at the single-molecule level is becoming more and more important for a better understanding of biological processes and diseases. In this work, the aptamer-functionalized nanopore was prepared as the sensing platform for kinetic analysis of the carcinoembryonic antigen (CEA) with its aptamers, which is an important cancer biomarker. CEA molecules were captured by the aptamers immobilized on the inner surface of the nanopore, and there was a complicated interaction between the CEA molecules and the aptamer, which is the process of association and dissociation. This could be used to measure the dynamics of aptamer-protein interactions without labeling. The kinetic analysis could be evaluated at the single-molecule level to interpret the dissociation constants of the binding and dissociation processes. Results showed that the translocation of CEA molecules in a functionalized nanopore had a deep blockades degree and long duration compared with nanopore modified with bare gold, which could be used for CEA sensing. This protein and protein-related interaction we designed provides new insights for evaluating the binding affinity, which will be beneficial for protein sensing and immunoassays.

Nanopore-Based Single-Entity Electrochemistry for the Label-Free Monitoring of Single-Molecule Glycoprotein-Boronate Affinity Interaction and Its Sensing Application.

Nanopipettes provide a promising confined space that enables advances in single-molecule analysis, and their unique conical tubular structure is also suitable for single-cell analysis. In this work, functionalized-nanopore-based single-entity electrochemistry (SEE) analysis tools were developed for the label-free monitoring of single-molecule glycoprotein-boronate affinity interaction for the first time, and immunoglobulin G (IgG, one of the important biomarkers for many diseases such as COVID-19 and cancers) was employed as the model glycoprotein. The principle of this method is based on a single glycoprotein molecule passing through 4-mercaptophenylboronic acid (4-MPBA)-modified nanopipettes under a bias voltage and in the meantime interacting with the boronate group from modified 4-MPBA. This translocation and affinity interaction process can generate distinguishable current blockade signals. Based on the statistical analysis of these signals, the equilibrium association constant (κa) of single-molecule glycoprotein-boronate affinity interaction was obtained. The results show that the κa of IgG in the confined nanopore at the single-molecule level is much larger than that measured in the open system at the ensemble level, which is possibly due to the enhanced multivalent synergistic binding in the restricted space. Moreover, the functionalized-nanopore-based SEE analysis tools were further applied for the label-free detection of IgG, and the results indicate that our method has potential application value for the detection of glycoproteins in real samples, which also paves way for the single-cell analysis of glycoproteins.

A systematic review and meta-analysis of neostigmine for urinary retention after surgeries.

Background: The aim of this research is to analyze the efficacy of neostigmine in the treatment of postoperative urinary retention (POUR). Methods: In this research, we screened multiple databases including PubMed, EMBASE, Web of Science, and Chinese National Knowledge Infrastructure (CNKI). After a systematic search process, data extraction was conducted. Review Manager 5.2 was adopted for meta-analysis, sensitivity analysis, and bias analysis. Results: After searching for articles, 20 eligible trials including 1,850 patients after surgery were extracted. Our results suggested that the neostigmine group had a higher effective rate for urinary retention than the Chinese traditional and physical therapy group (OR =7.47, 95% CI: 4.10-13.59, overall effect P<0.001). Further subgroup analysis showed that neostigmine acupoint injection was better than neostigmine intramuscular injection. Time to first voiding in the neostigmine acupoint injection group was shorter than that in the neostigmine intramuscular injection group (MD =-81.92, 95% CI: -130.13 to -33.70, overall P<0.001, I2=99% with random effects model). Furthermore, neostigmine acupoint injection improved urine excretion (MD =243.40, 95% CI: 201.62-285.18, overall P<0.0001) and reduced the residual urine volume (MD =-41.31, 95% CI: -58.05 to -24.58, overall P<0.001, I2=75% with random effects model). The results of the sensitivity analysis and publication bias showed that this research was robust and had little publication bias. Discussion: Our meta-analysis results suggest that neostigmine can effectively improve the symptoms of POUR and neostigmine acupoint injection may achieve a better therapeutic effect.

Enzyme-Encapsulated Zeolitic Imidazolate Frameworks Formed Inside the Single Glass Nanopore: Catalytic Performance and Sensing Application.

Metal-organic frameworks (MOFs) can improve the stability and activity of enzymes under the MOF encapsulation. However, it remains a challenge to explore the effects of the MOF environment on enzymatic activity in a confined space. In this work, we immobilized the enzyme inside a glass nanopore to study the catalytic activity and stability of the enzyme in the MOF environment. Horseradish peroxidase (HRP) is encapsulated in zeolitic imidazolate framework-90 (ZIF-90) and zeolitic imidazolate framework-8 (ZIF-8), which are used as the catalytic platforms. The HRP can catalyze 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt (ABTS) molecules to generate ABTS+ ions, and the change of the transmembrane ion current will be monitored in real time. As the concentration of H2O2 increases, the amount of produced ABTS+ will increase; thus, the ionic current increases. The effects of the MOF structure on enzyme activity and stability are also investigated. The HRP encapsulated in the MOF and modified inside the nanopore provides a novel and unlabeled design for studying enzymatic catalysis in a confined environment, which should have extensive applications in chemical-/bio-sensing, electrocatalysis, and fundamental electrochemistry.

Intrinsic Catalytic Activities from Single Enzyme@Metal-Organic Frameworks by Using a Stochastic Collision Electrochemical Technique.

Enzymes encapsulated in metal-organic frameworks (enzyme@MOFs), as a promising immobilized enzyme, were investigated for intrinsic catalytic activities at the single entity level via a stochastic collision electrochemical technique. Zeolitic imidazolate frameworks with amorphous (aZIF-8) and crystalline (ZIF-8) structures were chosen as model MOFs to encapsulate glucose oxidase (GOx). We carried out single enzyme@MOF nanoparticle (NP) collision experiments using the carbon ultramicroelectrode (CUME), which demonstrated that the catalytic activity of GOx@ZIF-8 NPs was much less than GOx@aZIF-8 NPs. Meanwhile, the kcat and TON per GOx in aZIF-8 NPs were obtained, revealing the intrinsic catalytic activity of GOx in aZIF-8 NPs at the single entity level. This strategy is the first approach for investigating enzyme@MOFs at a single entity level, which can not only broaden the horizons of single entity electrochemistry (SEE) but also provide further insights into research on electrochemistry, catalysis, and nanocomposites.

Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial.

Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 ± 0.77 in placebo group, -0.51 ± 0.71, -0.75 ± 0.73, and -0.57 ± 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c ≤7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.

Development of ICAR ATRP-Based Polymerization-Induced Self-Assembly and Its Application in the Preparation of Organic-Inorganic Nanoparticles.

The functionalization and application of nano-objects generated using a polymerization induced self-assembly (PISA) procedure is becoming a focus in recent years. In this contribution, using ethanol as solvent, poly(oligo(ethylene oxide) methyl ether methacrylate) (POEOMA) as macro-initiator/stabilizer, and 2-(perfluorohexyl)ethyl methacrylate (PFHEMA) and glycidyl methacrylate (GMA) as comonomers, the initiators for continuous activator regeneration atom transfer radical polymerization (ICAR ATRP)-based PISA is realized. The lower GMA content system tends to form spheres with large diameters and heavy contrast, while the lower PFHEMA content system tends to form the spheres or short worms with small diameters. However, the system with further increased GMA content results in the failed ICAR ATRP PISA procedure with the formation of precipitates by the cross-linking reaction between pendant epoxy groups. Furthermore, using the efficient reaction between the epoxy group on GMA and thiol group on mercapto-succinic acid agent, the carboxyl groups can be introduced into the inner cavity of the nano-objects and used for incorporation with the Fe2+ and Fe3+ ions, and the organic-inorganic nanoparticles Fe3 O4 @POEOMA are finally prepared in the presence of a reductant.

Novel manganese(II)-based metal-organic gels: synthesis, characterization and application to chemiluminescent sensing of hydrogen peroxide and glucose.

A metal-organic gel (MOG) was synthesized that is composed of manganese(II) as the central ion and 1,10-phenanthroline-2,9-dicarboxylic acid as the ligand. The resulting MOG exhibits excellent activity for catalyzing the chemiluminescence (CL) of the luminol/hydrogen peroxide system. The CL system was characterized by CL spectra, UV-vis absorption spectra and by studying potential interferences by common radical scavengers. The CL reaction was exploited in a new scheme for the determination of hydrogen peroxide. CL intensity increases linearly in the 0.4 µM ~ 3 mM hydrogen peroxide concentration range, and the limit of detection (LOD) is 0.12 µM. The method was extended to an enzymatic assay for glucose by using glucose oxidase and by measurement of the enzymatically formed hydrogen peroxide. The assay works in the 0.2 µM ~ 3 mM glucose concentration range, and the LOD is 0.08 µM. Graphical abstract Schematic representation of the synthesized Mn-containing MOGs catalyzing luminol-hydrogen peroxide chemiluminescent reaction, which can be used to establish a new CL method for the detection of hydrogen peroxide and glucose.

ICAR ATRP Polymerization-Induced Self-Assembly Using a Mixture of Macroinitiator/Stabilizer with Different Molecular Weights.

The poly[oligo(ethylene oxide) methyl ether methacrylate]s, POEOMA24 and POEOMA78 with average degree of polymerization (DP) of 24 and 78, respectively, are separately achieved by initiators for continuous activator regeneration (ICAR) atom transfer radical polymerization (ATRP) of OEOMA300 monomer. The mixtures of [POEOMA24 ]0 /[POEOMA78 ]0 = 1/1, 2/1, or 4/1 are employed as macroinitiator/stabilizer to practice the ICAR ATRP polymerization-induced self-assembly (PISA) of benzyl methacrylate (BnMA) at 65 °C. When the obtained dispersions are sequentially cooled to room temperature, diluted into ethanol, and observed by transmission electron microscopy (TEM) measurement, the cases of [POEOMA24 ]0 /[POEOMA78 ]0 = 1/1 or 2/1 and target DPPB n MA = 100 or 200 lead to nanoparticles with irregular sizes, while the cases of [POEOMA24 ]0 /[POEOMA78 ]0 = 4/1 and target DPPB n MA = 300 give the regular ones. When the obtained dispersions at a high temperature (65 °C) are directly diluted into room temperature ethanol and observed by TEM, nanoparticles with light contrast but clear contour can be observed. The results show that the higher content of POEOMA78 tends to improve the solubility of diblock copolymer and thus leads to insufficient stabilization of the nanoparticles. The morphological difference from the room-temperature and 65 °C dispersions help elucidate the intrinsic character of the PISA system.

Activation of AMP-activated protein kinase (AMPK) aggravated postoperative cognitive dysfunction and pathogenesis in aged rats.

The upstream signal molecule modulating neuro-inflammation and synaptic changes during the pathogenesis of postoperative cognitive dysfunction (POCD) is still elusive. Here, we examined the effects and mechanisms of energy sensor AMP-activated protein kinase (AMPK) in the pathogenesis of POCD. Our data showed that surgery significantly increased the expression of p-AMPK in aged rats (p < 0.05), but not in adult rats (p > 0.05). Moreover, inhibiting AMPK activation via compound C during operation significantly improved surgery-induced impairment of the learning and memory of aged rats in water maze (p < 0.05). Further mechanism studies showed that corresponding to the impairment of learning and memory after surgery, surgery significantly increased the activation of microglia, decreased the expressions of NR2B and p-NR2B, and increased the expressions of Tau and p-Tau, which also were obviously restored by inhibiting AMPK during operation. In contrast, Inhibiting AMPK activation during operation didn't change ATP level in the hippocampus of aged rats after surgery. These data suggest that surgery induced activation of AMPK in hippocampus in an age-dependent manner. AMPK plays important roles in POCD of aged rats via multiple mechanisms, and is a possible molecular target for the prevention and treatment of POCD.

Synthesis of star-like hybrid POSS-(PDMAEMA-b-PDLA)8 copolymer and its stereocomplex properties with PLLA.

Although poly(lactide) (PLA), when used as biomaterials, possesses many good properties, its high hydrophobicity and slow degradation may hinder its applications. In this work, a novel star-like oligomeric silsesquioxane-(poly(2-dimethylaminoethyl methacrylate)-b-poly(d-lactide))8 (POSS-(PDMAEMA-b-PDLA)8) was first synthesized through a three-step procedure that involves Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization of DMAEMA initiated by the macroinitiator POSS-8-CTA, and then conversion of the trithiocarbonated end groups on PDMAEMA arms into hydroxyl groups by a combination of aminolysis and Michael addition followed by controlled ring-opening polymerization of D-LA. In the next step, the synthesized hybrid copolymer POSS-(PDMAEMA-b-PDLA)8 was blended with PLLA in solution to form nanocomposites to further modify the thermo-mechanical and degradation properties of PLLA. It was noted that the outer PDLA shell could facilitate POSS-(PDMAEMA-b-PDLA)8 to be well-dispersed in PLLA matrix through stereocomplex (SC) interaction, and the inner PDMAEMA shell endowed PLLA with good hydrophilicity. The SC formation between POSS-(PDMAEMA-b-PDLA)8 and PLLA was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses. The surface wettability of the PLLA was enhanced due to the presence of hydrophilic PDMAEMA segments and the contact angle values decreased with increasing amount of PDMAEMA in the nanocomposites. Meanwhile, controlled degradation of PLLA in a faster pace was achieved when the nanocomposites were incubated in different pH solutions, indicating its potential in specific biomedical applications.

Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats.

Postoperative neurocognitive disorders are common complications in elderly patients following surgery or critical illness. High mobility group box 1 protein (HMGB1) is rapidly released after tissue trauma and critically involved in response to sterile injury. Herein, we assessed the role of HMGB1 after liver surgery in aged rats and explored the therapeutic potential of a neutralizing anti-HMGB1 monoclonal antibody in a clinically relevant model of postoperative neurocognitive disorders. Nineteen to twenty-two months Sprague-Dawley rats were randomly assigned as: (1) control with saline; (2) surgery, a partial hepatolobectomy under sevoflurane anesthesia and analgesia, + immunoglobulin G as control antibody; (3) surgery + anti-HMGB1. A separate cohort of animals was used to detect His-tagged HMGB1 in the brain. Systemic anti-HMGB1 antibody treatment exerted neuroprotective effects preventing postoperative memory deficits and anxiety in aged rats by preventing surgery-induced reduction of phosphorylated cyclic AMP response element-binding protein in the hippocampus. Although no evident changes in the intracellular distribution of HMGB1 in hippocampal cells were noted after surgery, HMGB1 levels were elevated on day 3 in rat plasma samples. Experiments with tagged HMGB1 further revealed a critical role of systemic HMGB1 to enable an access to the brain and causing microglial activation. Overall, these data demonstrate a pivotal role for systemic HMGB1 in mediating postoperative neuroinflammation. This may have direct implications for common postoperative complications like delirium and postoperative cognitive dysfunction.