Oxygen influences spatial heterogeneity and microbial succession dynamics during Baijiu stacking process.

The spontaneous solid-state stacking process (SSSP) of Baijiu is an environmentally friendly and cost-effective process for enriching and assembling environmental microorganisms to guarantee the subsequent fermentation efficiency. In this study, how SSSP create spatial heterogeneity of stacking piles were found through spatiotemporal sampling. The degree of difficulty in oxygen exchange categorizes the stacking pile into depleted (≤4%), transitional (4 %-17 %), and enriched (≥17 %) oxygen-defined layers. This results in variation in succession rates (Vdepleted > Vtransitional > Venriched), which accelerates spatial heterogeneity during SSSP. As a dominant species (65 %-99 %) in depleted and transitional layers, Acetilactobacillus jinshanensis can rapidly reduce oxygen disturbance by upregulating poxL and catE, that sustains spatial heterogeneity. The findings demonstrated the value of oxygen control in shaping spatial heterogeneity during SSSP processes, which can create specific functional microbiome. Adding spatial heterogeneity management will help achieve more precise control of such solid-state fermentation systems.

Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes.

BACKGROUND: Circulating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. OBJECTIVES: We aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. METHODS: Histone-fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). RESULTS: Fibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 µg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate-severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. CONCLUSION: Fibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

Nonlinear dynamics of postural control system under visual-vestibular habituation balance practice: evidence from EEG, EMG and center of pressure signals.

Human postural control system is inherently complex with nonlinear interaction among multiple subsystems. Accordingly, such postural control system has the flexibility in adaptation to complex environments. Previous studies applied complexity-based methods to analyze center of pressure (COP) to explore nonlinear dynamics of postural sway under changing environments, but direct evidence from central nervous system or muscular system is limited in the existing literature. Therefore, we assessed the fractal dimension of COP, surface electromyographic (sEMG) and electroencephalogram (EEG) signals under visual-vestibular habituation balance practice. We combined a rotating platform and a virtual reality headset to present visual-vestibular congruent or incongruent conditions. We asked participants to undergo repeated exposure to either congruent (n = 14) or incongruent condition (n = 13) five times while maintaining balance. We found repeated practice under both congruent and incongruent conditions increased the complexity of high-frequency (0.5-20 Hz) component of COP data and the complexity of sEMG data from tibialis anterior muscle. In contrast, repeated practice under conflicts decreased the complexity of low-frequency (<0.5 Hz) component of COP data and the complexity of EEG data of parietal and occipital lobes, while repeated practice under congruent environment decreased the complexity of EEG data of parietal and temporal lobes. These results suggested nonlinear dynamics of cortical activity differed after balance practice under congruent and incongruent environments. Also, we found a positive correlation (1) between the complexity of high-frequency component of COP and the complexity of sEMG signals from calf muscles, and (2) between the complexity of low-frequency component of COP and the complexity of EEG signals. These results suggested the low- or high-component of COP might be related to central or muscular adjustment of postural control, respectively.

Microclots, as defined by amyloid-fibrinogen aggregates, predict risks of disseminated intravascular coagulation and mortality.

ABSTRACT: Microclots have been associated with various conditions, including postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection. They have been postulated to be amyloid-fibrin(ogen) aggregates, but their role as a prognostic biomarker remains unclear. To examine their possible clinical utility, blood samples were collected for the first 96 hours from critically ill patients (n = 104) admitted to the intensive care unit (ICU). Detection was by staining platelet-poor plasma samples with thioflavin T and visualized by fluorescent microscopy. Image J software was trained to identify and quantify microclots, which were detected in 44 patients (42.3%) on ICU admission but not in the remaining 60 (57.7%) or the 20 healthy controls (0.0%). Microclots on admission to ICU were associated with a primary diagnosis of sepsis (microclots present in sepsis, 23/44 [52.3%] vs microclots absent in sepsis, 19/60 [31.7%]; P = .044). Multicolor immunofluorescence demonstrated that microclots consisted of amyloid-fibrinogen aggregates, which was supported by proteomic analysis. Patients with either a high number or larger-sized microclots had a higher likelihood of developing disseminated intravascular coagulation (odds ratio [OR], 51.4; 95% confidence interval [CI], 6.3-6721.1; P < .001) and had an increased probability of 28-day mortality (OR, 5.3; 95% CI, 2.0-15.6; P < .001). This study concludes that microclots, as defined by amyloid-fibrin(ogen) aggregates, are potentially useful in identifying sepsis and predicting adverse coagulopathic and clinical outcomes.

Analysis of Amplitude Modulation of EEG Based on Holo-Hilbert Spectrum Analysis During General Anesthesia.

OBJECTIVE: The study aims to investigate the relationship between amplitude modulation (AM) of EEG and anesthesia depth during general anesthesia. METHODS: In this study, Holo-Hilbert spectrum analysis (HHSA) was used to decompose the multichannel EEG signals of 15 patients to obtain the spatial distribution of AM in the brain. Subsequently, HHSA was applied to the prefrontal EEG (Fp1) obtained during general anesthesia surgery in 15 and 34 patients, and the α-θ and α-δ regions of feature (ROFs) were defined in Holo-Hilbert spectrum (HHS) and three features were derived to quantify AM in ROFs. RESULTS: During anesthetized phase, an anteriorization of the spatial distribution of AMs of α-carrier in brain was observed, as well as AMs of α-θ and α-δ in the EEG of Fp1. The total power ([Formula: see text]), mean carrier frequency ([Formula: see text]) and mean amplitude frequency ([Formula: see text]) of AMs changed during different anesthesia states. CONCLUSION: HHSA can effectively analyze the cross-frequency coupling of EEG during anesthesia and the AM features may be applied to anesthesia monitoring. SIGNIFICANCE: The study provides a new perspective for the characterization of brain states during general anesthesia, which is of great significance for exploring new features of anesthesia monitoring.

Multisensory Conflict Impairs Cortico-Muscular Network Connectivity and Postural Stability: Insights from Partial Directed Coherence Analysis.

Sensory conflict impacts postural control, yet its effect on cortico-muscular interaction remains underexplored. We aimed to investigate sensory conflict's influence on the cortico-muscular network and postural stability. We used a rotating platform and virtual reality to present subjects with congruent and incongruent sensory input, recorded EEG (electroencephalogram) and EMG (electromyogram) data, and constructed a directed connectivity network. The results suggest that, compared to sensory congruence, during sensory conflict: (1) connectivity among the sensorimotor, visual, and posterior parietal cortex generally decreases, (2) cortical control over the muscles is weakened, (3) feedback from muscles to the cortex is strengthened, and (4) the range of body sway increases and its complexity decreases. These results underline the intricate effects of sensory conflict on cortico-muscular networks. During the sensory conflict, the brain adaptively decreases the integration of conflicting information. Without this integrated information, cortical control over muscles may be lessened, whereas the muscle feedback may be enhanced in compensation.

Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. METHODS: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. RESULTS: There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. CONCLUSION: The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.

[The effect of visual-vestibular sensory input consistency on standing stability and electroencephalogram brain network characteristics in the elderly].

Aging is a crucial factor influencing postural stability control and contributing to frequent falls, yet its underlying mechanisms remain incompletely understood. This study aims to explore the effects of aging on postural stability control by comparing differences in postural stability and node strength of electroencephalogram (EEG) brain network between elderly and young people under the conditions of congruent and incongruent visual-vestibular sensory inputs. Eighteen elderly volunteers without neuromuscular disorders and eighteen young individuals participated in the present study. Virtual reality (VR) technology was employed to manipulate visual rotation stimuli (clockwise and counterclockwise), and a horizontal rotating platform was used for vestibular rotation stimuli (clockwise). Based on the directional disparity of sensory input in the horizontal plane, visual-vestibular input consistency was categorized as congruent and incongruent. Postural stability was assessed by the center of pressure (COP) trajectory, and EEG signals were collected and analyzed using directed network analysis to observe EEG brain network node connectivity strength. The results revealed that, under conditions of incongruent visual-vestibular sensory inputs, the elderly exhibited significantly inferior postural stability performance in terms of COP anterior-posterior (Y-axial) sway speed, total path length, anterior-posterior and medial-lateral sample entropy, compared to the young adults. Moreover, the node connectivity strength of visual cortex in the elderly was notably higher, while node connectivity strength of superior temporal cortex was significantly lower than that in the young adults. These findings suggest that the elderly have a heightened reliance on visual information in postural control and an impaired ability to cope with sensory conflicts arising from incongruent visual-vestibular sensory inputs, leading to compromised postural stability. The outcomes of this study hold significant implications for future assessments of balance function in the elder and fall prevention trainings.

Immune dysregulation in sepsis: experiences, lessons and perspectives.

Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.

Development of genomic phenotype and immunophenotype of acute respiratory distress syndrome using autophagy and metabolism-related genes.

Background: Distinguishing ARDS phenotypes is of great importance for its precise treatment. In the study, we attempted to ascertain its phenotypes based on metabolic and autophagy-related genes and infiltrated immune cells. Methods: Transcription datasets of ARDS patients were obtained from Gene expression omnibus (GEO), autophagy and metabolic-related genes were from the Human Autophagy Database and the GeneCards Database, respectively. Autophagy and metabolism-related differentially expressed genes (AMRDEGs) were further identified by machine learning and processed for constructing the nomogram and the risk prediction model. Functional enrichment analyses of differentially expressed genes were performed between high- and low-risk groups. According to the protein-protein interaction network, these hub genes closely linked to increased risk of ARDS were identified with CytoHubba. ssGSEA and CIBERSORT was applied to analyze the infiltration pattern of immune cells in ARDS. Afterwards, immunologically characterized and molecular phenotypes were constructed according to infiltrated immune cells and hub genes. Results: A total of 26 AMRDEGs were obtained, and CTSB and EEF2 were identified as crucial AMRDEGs. The predictive capability of the risk score, calculated based on the expression levels of CTSB and EEF2, was robust for ARDS in both the discovery cohort (AUC = 1) and the validation cohort (AUC = 0.826). The mean risk score was determined to be 2.231332, and based on this score, patients were classified into high-risk and low-risk groups. 371 differential genes in high- and low-risk groups were analyzed. ITGAM, TYROBP, ITGB2, SPI1, PLEK, FGR, MPO, S100A12, HCK, and MYC were identified as hub genes. A total of 12 infiltrated immune cells were differentially expressed and have correlations with hub genes. According to hub genes and implanted immune cells, ARDS patients were divided into two different molecular phenotypes (Group 1: n = 38; Group 2: n = 19) and two immune phenotypes (Cluster1: n = 22; Cluster2: n = 35), respectively. Conclusion: This study picked up hub genes of ARDS related to autophagy and metabolism and clustered ARDS patients into different molecular phenotypes and immunophenotypes, providing insights into the precision medicine of treating patients with ARDS.

Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells.

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10-100 nM concentration range (Fisher's Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.

Cell-free histones and the cell-based model of coagulation.

The cell-based model of coagulation remains the basis of our current understanding of clinical hemostasis and thrombosis. Its advancement on the coagulation cascade model has enabled new prohemostatic and anticoagulant treatments to be developed. In the past decade, there has been increasing evidence of the procoagulant properties of extracellular, cell-free histones (CFHs). Although high levels of circulating CFHs released following extensive cell death in acute critical illnesses, such as sepsis and trauma, have been associated with adverse coagulation outcomes, including disseminated intravascular coagulation, new information has also emerged on how its local effects contribute to physiological clot formation. CFHs initiate coagulation by tissue factor exposure, either by destruction of the endovascular barrier or induction of endoluminal tissue factor expression on endothelia and monocytes. CFHs can also bind prothrombin directly, generating thrombin via the alternative prothrombinase pathway. In amplifying and augmenting the procoagulant signal, CFHs activate and aggregate platelets, increase procoagulant material bioavailability through platelet degranulation and Weibel-Palade body exocytosis, activate intrinsic coagulation via platelet polyphosphate release, and induce phosphatidylserine exposure. CFHs also inhibit protein C activation and downregulate thrombomodulin expression to reduce anti-inflammatory and anticoagulant effects. In consolidating clot formation, CFHs augment the fibrin polymer to confer fibrinolytic resistance and integrate neutrophil extracellular traps into the clot structure. Such new information holds the promise of new therapeutic developments, including improved targeting of immunothrombotic pathologies in acute critical illnesses.

Non-gene-editing microbiome engineering of spontaneous food fermentation microbiota-Limitation control, design control, and integration.

Non-gene-editing microbiome engineering (NgeME) is the rational design and control of natural microbial consortia to perform desired functions. Traditional NgeME approaches use selected environmental variables to force natural microbial consortia to perform the desired functions. Spontaneous food fermentation, the oldest kind of traditional NgeME, transforms foods into various fermented products using natural microbial networks. In traditional NgeME, spontaneous food fermentation microbiotas (SFFMs) are typically formed and controlled manually by the establishment of limiting factors in small batches with little mechanization. However, limitation control generally leads to trade-offs between efficiency and the quality of fermentation. Modern NgeME approaches based on synthetic microbial ecology have been developed using designed microbial communities to explore assembly mechanisms and target functional enhancement of SFFMs. This has greatly improved our understanding of microbiota control, but such approaches still have shortcomings compared to traditional NgeME. Here, we comprehensively describe research on mechanisms and control strategies for SFFMs based on traditional and modern NgeME. We discuss the ecological and engineering principles of the two approaches to enhance the understanding of how best to control SFFM. We also review recent applied and theoretical research on modern NgeME and propose an integrated in vitro synthetic microbiota model to bridge gaps between limitation control and design control for SFFM.

Extracellular Histone-Induced Protein Kinase C Alpha Activation and Troponin Phosphorylation Is a Potential Mechanism of Cardiac Contractility Depression in Sepsis.

Reduction in cardiac contractility is common in severe sepsis. However, the pathological mechanism is still not fully understood. Recently it has been found that circulating histones released after extensive immune cell death play important roles in multiple organ injury and disfunction, particularly in cardiomyocyte injury and contractility reduction. How extracellular histones cause cardiac contractility depression is still not fully clear. In this work, using cultured cardiomyocytes and a histone infusion mouse model, we demonstrate that clinically relevant histone concentrations cause significant increases in intracellular calcium concentrations with subsequent activation and enriched localization of calcium-dependent protein kinase C (PKC) α and ßII into the myofilament fraction of cardiomyocytes in vitro and in vivo. Furthermore, histones induced dose-dependent phosphorylation of cardiac troponin I (cTnI) at the PKC-regulated phosphorylation residues (S43 and T144) in cultured cardiomyocytes, which was also confirmed in murine cardiomyocytes following intravenous histone injection. Specific inhibitors against PKCα and PKCßII revealed that histone-induced cTnI phosphorylation was mainly mediated by PKCα activation, but not PKCßII. Blocking PKCα also significantly abrogated histone-induced deterioration in peak shortening, duration and the velocity of shortening, and re-lengthening of cardiomyocyte contractility. These in vitro and in vivo findings collectively indicate a potential mechanism of histone-induced cardiomyocyte dysfunction driven by PKCα activation with subsequent enhanced phosphorylation of cTnI. These findings also indicate a potential mechanism of clinical cardiac dysfunction in sepsis and other critical illnesses with high levels of circulating histones, which holds the potential translational benefit to these patients by targeting circulating histones and downstream pathways.

An integrated information theory index using multichannel EEG for evaluating various states of consciousness under anesthesia.

BACKGROUND: The integrated information theory (IIT) of consciousness introduces a measure Φ to quantify consciousness in a physical system. Directly related to this, general anesthesia aims to induce reversible and safe loss of consciousness (LOC). We sought to propose an electroencephalogram (EEG)-based IIT index ΦEEG to evaluate various states of consciousness under general anesthesia. METHODS: Based on the definition of mutual information, we estimated the ΦEEG by maximizing the integrated information under various time lags. We used the binning method to cut the nonGaussian EEG data for estimating mutual information. We tested two EEG databases collected from propofol- (n=20) and sevoflurane-induced (n=15) anesthesia, and especially, we compared the ΦEEG of drowsy (n=7) and responsive participants (n=13) under propofol anesthesia. We compared the effectiveness of ΦEEG with the estimated bispectral index (eBIS). RESULTS: In all EEG frequency bands, we observed a negative correlation between ΦEEG and end-tidal sevoflurane concentration under sevoflurane-induced anesthesia (p<0.001,BF10>6000). Under propofol-induced anesthesia, drowsy participants in moderate sedation (6.96±0.26(mean±SD)) showed decreased alpha-band ΦEEG compared with baseline (7.40±0.53,p=0.016,BF10=3.58), no significant difference was observed for responsive participants. Oppositely, the responsive participants in moderate sedation (-5.32±0.38) showed decreased eBIS compared with baseline (-4.94±0.40,p=0.03,BF10=2.41). CONCLUSIONS: These findings may enable monitors of the anesthetic state that can distinguish consciousness and unconsciousness rather than the changes of anesthetic concentrations. The alpha-band ΦEEG is promising for deriving the gold standard for depth of anesthesia monitoring.

Recovery of Brain Network Integration and Segregation During the Loss and Recovery of Consciousness Induced by Sevoflurane.

Anesthetic-induced loss of consciousness (LOC) has been studied using functional connectivity (FC) and functional network analysis (FNA), manifested as fragmentation of the whole-brain functional network. However, how the fragmented brain networks reversibly recover during the recovery of consciousness (ROC) remains vague. This study aims to investigate the changes in brain network structure during ROC, to better understand the network fragmentation during anesthesia, thus providing insights into consciousness monitoring. We analyzed EEG data recorded from 15 individuals anesthetized by sevoflurane. By investigating the properties of functional networks generated using different brain atlases and performing community detection for functional networks, we explored the changes in brain network structure to understand how fragmented brain networks recover during the ROC. We observed an overall larger FC magnitude during LOC than in the conscious state. The ROC was accompanied by the increasing binary network efficiency, decreasing FC magnitude, and decreasing community similarity with the functional atlas. Furthermore, we observed a negative correlation between modularity and community number ( [Formula: see text] and , linear regression test), in which modularity increased and community number decreased during ROC. Our results show that a larger FC magnitude reveals excessive synchronization of neuronal activities during LOC. The increasing binary network efficiency, decreasing community number, and decreasing community similarity indicate the recovery of functional network integration. The increasing modularity implies the recovery of functional network segregation during ROC. The results suggest the limitation of FC magnitude and modularity in monitoring anesthetized states and the potential of integrated information theory to evaluate consciousness.

The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction.

BACKGROUND: Multiple organ injury and dysfunction often occurs in acute critical illness and adversely affects survival. However, in patients who survive, organ function usually recovers without permanent damage. It is, therefore, likely that there are reversible mechanisms, but this is poorly understood in the pathogenesis of multiple organ dysfunction syndrome (MODS). AIMS: Based on our knowledge of extracellular histones and pneumolysin, as endogenous and exogenous pore-forming toxins, respectively, here we clarify if the extent of cell membrane disruption and recovery is important in MODS. METHODS: This is a combination of retrospective clinical studies of a cohort of 98 patients from an intensive care unit (ICU) in a tertiary hospital, with interventional animal models and laboratory investigation. RESULTS: In patients without septic shock and/or disseminate intravascular coagulation (DIC), circulating histones also strongly correlated with sequential organ failure assessment (SOFA) scores, suggesting their pore-forming property might play an important role. In vivo, histones or pneumolysin infusion similarly caused significant elevation of cell damage markers and multiple organ injury. In trauma and sepsis models, circulating histones strongly correlated with these markers, and anti-histone reagents significantly reduced their release. Comparison of pneumolysin deletion and its parental strain-induced sepsis mouse model showed that pneumolysin was not essential for sepsis development, but enhanced multiple organ damage and reduced survival time. In vitro, histones and pneumolysin treatment disrupt cell membrane integrity, resulting in changes in whole-cell currents and elevated intracellular Ca2+ to lead to Ca2+ overload. Cell-specific damage markers, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and cardiac troponin I (cTnI), were released from damaged cells. Once toxins were removed, cell membrane damage could be rapidly repaired and cellular function recovered. CONCLUSION: This work has confirmed the importance of pore-forming toxins in the development of MODS and proposed a potential mechanism to explain the reversibility of MODS. This may form the foundation for the development of effective therapies.

Dynamic changes of brain networks during standing balance control under visual conflict.

Stance balance control requires a very accurate tuning and combination of visual, vestibular, and proprioceptive inputs, and conflict among these sensory systems may induce posture instability and even falls. Although there are many human mechanics and psychophysical studies for this phenomenon, the effects of sensory conflict on brain networks and its underlying neural mechanisms are still unclear. Here, we combined a rotating platform and a virtual reality (VR) headset to control the participants' physical and visual motion states, presenting them with incongruous (sensory conflict) or congruous (normal control) physical-visual stimuli. Further, to investigate the effects of sensory conflict on stance stability and brain networks, we recorded and calculated the effective connectivity of source-level electroencephalogram (EEG) and the average velocity of the plantar center of pressure (COP) in healthy subjects (18 subjects: 10 males, 8 females). First, our results showed that sensory conflict did have a detrimental effect on stance posture control [sensor F(1, 17) = 13.34, P = 0.0019], but this effect decreases over time [window*sensor F(2, 34) = 6.72, P = 0.0035]. Humans show a marked adaptation to sensory conflict. In addition, we found that human adaptation to the sensory conflict was associated with changes in the cortical network. At the stimulus onset, congruent and incongruent stimuli had similar effects on brain networks. In both cases, there was a significant increase in information interaction centered on the frontal cortices (p < 0.05). Then, after a time window, synchronized with the restoration of stance stability under conflict, the connectivity of large brain regions, including posterior parietal, visual, somatosensory, and motor cortices, was generally lower in sensory conflict than in controls (p < 0.05). But the influence of the superior temporal lobe on other cortices was significantly increased. Overall, we speculate that a posterior parietal-centered cortical network may play a key role in integrating congruous sensory information. Furthermore, the dissociation of this network may reflect a flexible multisensory interaction strategy that is critical for human posture balance control in complex and changing environments. In addition, the superior temporal lobe may play a key role in processing conflicting sensory information.

Dynamic alpha-gamma phase-amplitude coupling signatures during sevoflurane-induced loss and recovery of consciousness.

Phase-amplitude coupling (PAC) plays an important role in anesthetic-induced unconsciousness. The delta-alpha PAC signature during anesthetic-induced unconsciousness is gradually becoming known; however, the frequency dependence and spatial characteristics of PAC are still unclear. Multi-channel electroencephalography (EEG) was performed during the loss and recovery phases of consciousness in patients undergoing general anesthesia using sevoflurane. First, a spectral analysis was used to investigate the power change of the different frequency bands in the EEG signals. Second, PAC comodulogram analysis was performed to confirm the frequencies of the PAC phase drivers. Finally, to investigate the spatial characteristics of PAC, a novel PAC network was constructed using within- and cross-lead PAC, and a K-means clustering algorithm was used to identify PAC network patterns. Our results show that, in addition to the delta-alpha PAC, unconsciousness induced by sevoflurane was accompanied by spatial non-uniform alpha-gamma PAC in the cortical network, and dynamic PAC patterns between the anterior and posterior brain were observed during the unconscious phase. The dynamic transition of PAC network patterns indicates that brain states under sevoflurane-induced unconsciousness emerge from the regulation of functional integration and segregation instantiated by delta-alpha and alpha-gamma PAC.