Cationic ribosomal proteins can inhibit pro-inflammatory action stimulated by LPS+HMGB1 and are hindered by advanced glycation end products.

We previously found that ribosomal protein L9 (RPL9) is a novel advanced glycation end product (AGE)-binding protein that can decrease pro-inflammatory TNF-α expression stimulated by lipopolysaccharide (LPS) plus high-mobility group box 1 (HMGB1), suggesting that RPL9 has a role in regulating LPS+HMGB1-stimulated inflammatory reactions. Among the various ribosomal proteins, it was found that RPS5 reproduced the regulatory activity of RPL9 on LPS+HMGB1-stimulated TNF-α expression in macrophage-like RAW264.7 cells. RPL9 and RPS5 share a common feature as cationic proteins. Polylysine, a cationic polypeptide, and a synthetic peptide of the cationic region from RPL9 also exhibited reducing activity on LPS+HMGB1-induced TNF-α expression. By pull-down assay, RPL9 and RPS5 were confirmed to interact with AGEs. When AGEs coexisted with LPS, HMGB1, plus RPL9 or RPS5, the reducing effect of TNF-α expression by these cationic ribosomal proteins was shown to be abrogated. The results suggest that cationic ribosomal proteins have a regulatory role in the pro-inflammatory response induced by LPS+HMGB1, and in the pathophysiological condition of accumulating AGEs, this regulatory effect is abolished, which exacerbates inflammation.

Different modulation of STING/TBK1/IRF3 signaling by advanced glycation end products.

Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins.

Timecourse of two-dimensional decision-making to offensive actions.

Decision-making is an important component in the perception-action coupling required for athletes to achieve fine performance. Signal detection theory (SDT) provides a means of quantifying athletes' decision-making processes, based on their ability to discriminate between different types of stimuli (sensitivity) and the locations of their response criteria along a decision axis in a given situation. Studies have shown differences in these two indices between athletes and less-experienced counterparts, although these studies were limited to unidimensional decision-making problems. In the present study, SDT analysis was applied to two-dimensional decision-making by volleyball players regarding their opponents' attacks, using a four-alternative forced-choice task combining judgments of the type (spike or tip) and direction (cross-court or down-the-line) of attacks. Furthermore, a temporal occlusion task was used to reveal the timecourses of changes in sensitivity and the location of response criteria relating to judgments of attack type and direction. There were three groups of participants, eight top-league players, ten collegiate players, and ten novices. The results showed clear effects of expertise and distinct timecourses for the two types of judgment. For the attack type judgments, the sensitivities of the top-league players were relatively low at the early occlusion points, and their response criteria were biased toward judging attacking actions as spikes. At the late occlusion points, their sensitivity peaked, and there was no bias in their response criteria. For the directional judgments, the sensitivity of the three groups improved as the occlusion point advanced, while their response criteria tended to become more similar, which was not the case for the attack type judgments. These results are discussed together with previous studies of volleyball players' decision-making and judgments regarding deceptive actions in sports.

Histamine promotes angiogenesis through a histamine H1 receptor-PKC-VEGF-mediated pathway in human endothelial cells.

Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R-PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways.

Glycolaldehyde-derived advanced glycation end products promote macrophage proliferation via the JAK-STAT signaling pathway.

BACKGROUND: Advanced glycation end products (AGEs) are heterogeneous proinflammatory molecules produced by a non-enzymatic glycation reaction between reducing sugars (and their metabolites) and biomolecules with amino groups, such as proteins. Although increases in and the accumulation of AGEs have been implicated in the onset and exacerbation of lifestyle- or age-related diseases, including diabetes, their physiological functions have not yet been elucidated in detail. METHODS AND RESULTS: The present study investigated the cellular responses of the macrophage cell line RAW264.7 stimulated by glycolaldehyde-derived AGEs (Glycol-AGEs) known as representative toxic AGEs. The results obtained showed that Glycol-AGEs significantly promoted the proliferation of RAW264.7 cells at a low concentration range (1-10 µg/mL) in a concentration-dependent manner. On the other hand, neither TNF-α production nor cytotoxicity were induced by the same concentrations of Glycol-AGEs. The increases observed in cell proliferation by low concentrations of Glycol-AGEs were also detected in receptor triple knockout (RAGE-TLR4-TLR2 KO) cells as well as in wild-type cells. Increases in cell proliferation were not affected by various kinase inhibitors, including MAP kinase inhibitors, but were significantly suppressed by JAK2 and STAT5 inhibitors. In addition, the expression of some cell cycle-related genes was up-regulated by the stimulation with Glycol-AGEs. CONCLUSIONS: These results suggest a novel physiological role for AGEs in the promotion of cell proliferation via the JAK-STAT pathway.

Identification of ribosomal protein L9 as a novel regulator of proinflammatory damage-associated molecular pattern molecules.

BACKGROUND: We previously reported that advanced glycation endproducts (AGEs) increase the proinflammatory activity of high mobility group box-1 (HMGB1), a representative damage-associated molecular pattern molecule (DAMP), through their direct interaction. This suggested that AGEs activate other DAMPs and led us to search for novel DAMPs capable of interacting with AGEs. METHODS AND RESULTS: The chromatographic analysis using AGE-immobilized gel revealed the ribosomal protein family to be a factor with binding activity to AGEs. Ribosomal protein L9 (RPL9), a member of the ribosomal protein family, was found in the centrifugal supernatant of ruptured cells and in the serum of lipopolysaccharide (LPS)-stimulated sepsis model mice, exhibiting similar characteristic properties to HMGB1. Although HMGB1 potentiated LPS-stimulated TNF-α expression in macrophage-like RAW264.7 cells, RPL9 hardly exhibited this activity. Of note, RPL9 significantly suppressed the potentiated mRNA expression and protein production of TNF-α by HMGB1 plus LPS stimulation, suggesting its regulatory roles in DAMP-induced proinflammatory activity. Based on the differential scanning fluorimetric analysis, the direct interaction between RPL9 and HMGB1 may play a role in the suppressive effects of RPL9. CONCLUSIONS: This study suggested that RPL9 is a novel type of DAMP with a regulatory role in the proinflammatory response and provided insight into the pathophysiology of inflammatory diseases.

Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition.

BACKGROUND: Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor. METHODS: The inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells. RESULTS: NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its Ki value was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA. CONCLUSION: NDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition.

Involvement of multiple scavenger receptors in advanced glycation end product-induced vessel tube formation in endothelial cells.

Toxic advanced glycation end products (toxic AGEs) derived from glycolaldehyde (AGE3) have been implicated in the development of diabetic vascular complications such as retinopathy characterised by excessive angiogenesis. Different receptor types, such as receptor for AGEs (RAGE), Toll like receptor-4 and scavenger receptors, are expressed in endothelial cells and contribute to AGE-elicited alteration of cell function. In the present study, we examined the involvement of AGE-related receptors on AGE-induced angiogenesis in endothelial cells. The effects of pharmacological inhibitors or receptor neutralizing antibodies on AGE3-induced tube formation were investigated using the in vitro Matrigel tube formation assay in b.End5 cells (mouse endothelial cells). AGE3-induced signalling pathways and receptor expression changes were analysed by Western blot analysis and flow cytometry, respectively. Both FPS-ZM1, a RAGE inhibitor, and fucoidan, a ligand for scavenger receptors, suppressed AGE3-induced tube formation. Cocktails of neutralizing antibodies against the scavenger receptors CD36, CD163 and LOX-1 prevented AGE3-induced tube formation. AGE3 activated mTOR signalling, resulting in facilitation of tube formation. Activation of the AGE-RAGE pathway also led to the upregulation of scavenger receptors. Taken together, our findings suggest that the scavenger receptors CD36, CD163 and LOX-1 in conjunction with the RAGE receptor work together to mediate toxic AGE-induced facilitation of angiogenesis.

Alterations of lymphocyte count and platelet volume precede cerebrovascular lesions in stroke-prone spontaneously hypertensive rats.

Background: Cerebral small vessel disease (CSVD) is associated with future stroke. Although pathological alteration in small vessels of patients with CSVD can be detected by neuroimaging, diagnosis of CSVD is delayed because it is an asymptomatic disease. The stroke-prone spontaneously hypertensive rat (SHRSP) show similar pathological features to human CSVD and develop stroke-related symptoms with advancing age.Objective: We investigated the time course of haematological parameters in Wistar rats and SHRSP.Material and Methods: Blood cells were analysed using an automated haematological analyser.Results: SHRSP develop stroke-related symptoms including onset of neurological symptoms, decreased body weight and blood brain barrier leakage between 12 and 14 weeks of age. Lymphocyte counts were gradually decreased at 3 weeks before development of stoke-related symptoms and then were further decreased after the development of stroke-related symptoms. The both mean platelet volume and large platelet ratio gradually increased at 3 weeks before the development of stoke-related symptoms. However, although SHRSP showed more microcytic red cells than Wistar rats, the trajectories of change in erythrocyte-related parameters were similar between Wistar rats and SHRSP.Conclusion: Our pilot study suggests that alterations of lymphocyte count and platelet volume predictive indicators for asymptomatic CSVD and symptomatic stroke in SHRSP.

Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS) and high mobility group box-1 (HMGB1) through their direct interactions.

Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis. The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS-HMGB1 mixture synergistically potentiated LPS-HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS-HMGB1-AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs. Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS-HMGB1-stimulated proinflammatory response through direct interactions.

Differential contribution of possible pattern-recognition receptors to advanced glycation end product-induced cellular responses in macrophage-like RAW264.7 cells.

Advanced glycation end products (AGEs) are considered to be related to the pathogenesis of some inflammatory diseases. AGEs were reported to stimulate the receptor for AGEs (RAGE), which causes inflammatory reactions. However, recently, toll-like receptors (TLRs), in addition to RAGE, have been reported to be related to AGE-mediated cellular responses, and it remains unclear which receptor is responsible for AGE recognition. To reveal the role of pattern-recognition receptors, including TLRs and/or RAGE, in AGE-mediated cellular responses, we generated macrophage-like RAW264.7 knockout (KO) cells lacking these receptors by genome editing using the CRISPR/Cas9 system and assessed AGE-stimulated changes in these cells. Comparison of the established clones suggested that RAGE partially affects the expression of TLRs. In the KO clone lacking TLR4 and TLR2, AGE-stimulated tumor necrosis factor alpha (TNF-α) expression and phosphorylation of IκBα, p38, and extracellular signal-regulated kinase (ERK) were significantly attenuated, suggesting that AGE-mediated responses are largely dependent on TLRs. On the other hand, on comparison of the AGE-stimulated responses between the KO clone lacking TLR4 and TLR2, and the clone lacking TLR4, TLR2, and RAGE, RAGE played little role in AGE-stimulated TNF-α transcription and ERK phosphorylation. Taken together, this study suggested that AGE-stimulated inflammatory responses occur mainly through TLRs rather than RAGE.

The Effect of Augmented Feedback Type and Frequency on Velocity-Based Training-Induced Adaptation and Retention.

Nagata, A, Doma, K, Yamashita, D, Hasegawa, H, and Mori, S. The effect of augmented feedback type and frequency on velocity-based training-induced adaptation and retention. J Strength Cond Res 34(11): 3110-3117, 2020-The purpose of this study was to compare the benefits of 4 weeks of velocity-based training (VBT) using different augmented feedback (AugFb) types and the frequency of AugFb, and whether adaptations are retained 10 days post-training. Thirty-seven collegiate male rugby players were divided into groups that received immediate feedback (ImFb; n = 9), visual feedback (ViFb; n = 10), average feedback (AvgFb; n = 10) and no feedback (NoFb; n = 8) during each VBT session consisting of 3 sets of 5 repetitions of loaded jump squats. The ImFb group received AugFb regarding lifting velocity under loaded jump squats (LV-JS) after every jump, whereas LV-JS measures were averaged after each set of jumps and presented to the AvgFb group. The LV-JS were video-recorded and displayed as kinematic feedback for the ViFb group after each set, although NoFb was provided for the NoFb group. Loaded jump squats measures were reported at baseline, during each training session and 10 days post-training. Loaded jump squats measures were significantly greater for the ImFb Group compared with the other groups during a number of post-baseline time points (p ≤ 0.05). Furthermore, at 4 weeks of VBT and 10 days post-retention, effect size (ES) calculations showed that LV-JS measures were greater with moderate to large effects for the ImFb group compared with the NoFb (ES = 1.02-1.25), AvgFb (ES = 0.78-0.82) and ViFb (ES = 0.74-1.60), respectively. However, LV-JS measures were reduced with moderate to large effects 10 days post-retention for the ViFb (ES = -0.60) and NoFb (ES = -0.85) groups. Providing LV-JS feedback after each jump appears to optimize performance and should be considered as a training tool during VBT.

Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750.

Word scanning in native and non-native languages: insights into reading with declined accommodation.

This study investigated the effects of declined accommodation on reading performance in non-native and native languages. Eighteen native Japanese speakers participated: eight presbyopes and ten non-presbyopes. In the experiment, participants were asked to scan, or sequentially read six-word items presented in two-line texts, identify a non-word target as quickly as possible, and indicate its location. In addition to the participant type (presbyopes/non-presbyopes) and language of the reading material (Japanese/English), viewing distance (35 cm/70 cm) and contrast (18%/100%) were manipulated. The results showed that the presbyopes exhibited worse reading performance than the non-presbyopes at closer distances irrespective of the language. Notably, the inferiority of the presbyopes' reading performance was more pronounced when they read in a non-native language than in their native language. It should be noted that differences in reading performance between the presbyopes and non-presbyopes were subtle for high-contrast words at longer viewing distances, indicating that age- or cohort-related perceptual, motor, and cognitive differences were almost negligible, but accommodation mattered. These results suggest that the effect of accommodation decline is influenced by the language of the reading material.

Precision of voicing perceptual identification is altered in association with voice-onset time production changes.

There is ample evidence that motor learning changes the function of perceptual systems. Previous studies examining the interactions between speech production and perception have shown that the discrimination of phonetic contrasts characterized by the difference in articulatory place features is altered following their production changes caused by the perturbation of auditory feedback. The present study focused on a voiced-voiceless contrast in stop consonants, which is characterized by a temporal articulatory parameter, voice-onset time (VOT). In the experiment, we manipulated the participants' motor functions concerning VOT using a cross-categorical auditory feedback (CAF) paradigm (Mitsuya et al. in J Acoust Soc Am 135:2986-2994, 2014), in which a pre-recorded syllable sound starting with a voiced stop consonant (/da/) was fed back simultaneously with the participant's utterance of a voiceless stop consonant (/ta/), and vice versa. The VOT difference between /da/ and /ta/ productions was increased by the CAF, which is consistent with the result of Mitsuya's study. In addition, we conducted perceptual identification tasks of /da/-/ta/ continuum stimuli varying in VOT before and after the CAF task, and found that the identification function became sharper after as compared to before the CAF task. A significant positive correlation between such production and perception changes was also found. On the basis of these results, we consider that the change in motor function concerning VOT affected voiced-voiceless perceptual processing. The present study is the first to show the involvement of the speech production system in the perception of phonetic contrasts characterized by articulatory temporal features.

Anti-HMGB1 monoclonal antibody therapy for a wide range of CNS and PNS diseases.

High mobility group box-1 (HMGB1), a representative damage associated-molecular pattern (DAMP), has been reported to be involved in many inflammatory diseases. Several drugs are thought to have potential to control the translocation and secretion of HMGB1, or to neutralize extracellular HMGB1 by binding to it. One of these drugs, anti-HMGB1 monoclonal antibody (mAb), is highly specific for HMGB1 and has been shown to be effective for the treatment of a wide range of CNS diseases when modeled in animals, including stroke, traumatic brain injury, Parkinson's disease, epilepsy and Alzheimer's disease. Thus, anti-HMGB1 mAb not only is useful for target validation but also has extensive potential for the treatment of the above-mentioned diseases. In this review, we summarize existing knowledge on the effects of anti-HMGB1 mAb on CNS and PNS diseases, the common features of translocation and secretion of HMGB1 and the functional roles of HMGB1 in these diseases. The existing literature suggests that anti-HMGB1 mAb therapy would be effective for a wide range of CNS and PNS diseases.

The C-terminal region of tumor necrosis factor like weak inducer of apoptosis is required for interaction with advanced glycation end products.

Previously, we found that endogenously produced pro-inflammatory molecules, advanced glycation end products (AGEs), interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and attenuate its immunomodulatory function. In the present study, to elucidate the mechanism by which AGEs attenuate TWEAK function, we searched for regions responsible for TWEAK-AGE interaction using TWEAK deletion mutants. Pull-down assays with the TWEAK mutants and AGEs revealed that the C-terminal half of TWEAK, which is the region essential for receptor stimulation, was required for this interaction. On the other hand, the N-terminal deletion mutants did not exhibit a significant decrease in AGE binding. Moreover, a moderate decrease in the AGE binding by double-deletion in quartered C-terminal half regions and a substantial decrease by triple-deletion in this region were observed. In addition, full-length TWEAK stimulated IL-8 gene expression in endothelial EA.hy.926 cells, whereas the triple-deletion mutant lost much of this activity, suggesting that the TWEAK-AGE interaction sites overlap with the region needed to exert normal function of TWEAK. Our present findings may help to elucidate the pathophysiological roles of the TWEAK-AGE interaction for prevention and treatment of AGE-related inflammatory diseases.

Decrease in Histidine-Rich Glycoprotein as a Novel Biomarker to Predict Sepsis Among Systemic Inflammatory Response Syndrome.

OBJECTIVES: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. DESIGN: Single-center, prospective, observational cohort study. SETTING: ICU at an university-affiliated hospital. PATIENTS: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. CONCLUSIONS: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Effects of Histidine-rich glycoprotein on erythrocyte aggregation and hemolysis: Implications for a role under septic conditions.

The apoptotic process of erythrocytes is known as eryptosis, and is characterized by phosphatidylserine (PS) expression on the outer membrane. PS-positive erythrocytes are increased in sepsis, and PS is believed to facilitate coagulation of erythrocytes and activate macrophages. However, the relationship between eryptosis and abnormal coagulation in sepsis is still not fully understood. Histidine-rich glycoprotein (HRG) inhibits immunothrombus formation by regulating neutrophils and vascular endothelial cells. In the present study, we subjected isolated erythrocytes to Zn2+ stimulation, which activated their aggregation and PS expression. We then determined the Zn2+ contents in septic lung and kidney tissues, and found that they were elevated, suggesting that eryptosis was enhanced in these tissues. Erythrocyte adhesion to endothelial cells was also significantly increased after Zn2+ stimulation, and this effect was inhibited by HRG. Finally, we examined HRG treatment in septic model mice, and found that HRG decreased hemolysis, possibly due to its ability to bind heme. Our study demonstrated a novel Zn2+-initiated aggregation/thrombus formation pathway. We also showed the regulatory role of HRG in this pathway, together with the ability of HRG to inhibit hemolysis under septic conditions. HRG supplementation might be a novel therapeutic strategy for inflammatory disorders, especially sepsis.

Auditory gap detection: psychometric functions and insights into the underlying neural activity.

The detection of a silent interval or gap provides important insight into temporal processing by the auditory system. Previous research has uncovered a multitude of empirical findings leaving the mechanism of gap detection poorly understood and key issues unresolved. Here, we expand the findings by measuring psychometric functions for a number of conditions including both across-frequency and across-intensity gap detection as a first study of its kind. A model is presented which not only accounts for our findings in a quantitative manner, but also helps frame the body of work on auditory gap research. The model is based on the peripheral response and postulates that the identification of gap requires the detection of activity associated with silence.