Transforming growth factor-beta 1 enhances discharge activity of cortical neurons.

JOURNAL/nrgr/04.03/01300535-202502000-00031/figure1/v/2024-05-28T214302Z/r/image-tiff Transforming growth factor-beta 1 (TGF-ß1) has been extensively studied for its pleiotropic effects on central nervous system diseases. The neuroprotective or neurotoxic effects of TGF-ß1 in specific brain areas may depend on the pathological process and cell types involved. Voltage-gated sodium channels (VGSCs) are essential ion channels for the generation of action potentials in neurons, and are involved in various neuroexcitation-related diseases. However, the effects of TGF-ß1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear. In this study, we investigated the effects of TGF-ß1 on VGSC function and firing properties in primary cortical neurons from mice. We found that TGF-ß1 increased VGSC current density in a dose- and time-dependent manner, which was attributable to the upregulation of Nav1.3 expression. Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase (PD98059), p38 mitogen-activated protein kinase (SB203580), and Jun NH2-terminal kinase 1/2 inhibitor (SP600125). Interestingly, TGF-ß1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons. These findings suggest that TGF-ß1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway, which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions. Thus, this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

Spatially Resolved Light-Induced Ferroelectric Polarization in α-In2Se3/Te Heterojunctions.

Light-induced ferroelectric polarization in 2D layered ferroelectric materials holds promise in photodetectors with multilevel current and reconfigurable capabilities. However, translating this potential into practical applications for high-density optoelectronic information storage remains challenging. In this work, an α-In2Se3/Te heterojunction design that demonstrates spatially resolved, multilevel, nonvolatile photoresponsivity is presented. Using photocurrent mapping, the spatially localized light-induced poling state (LIPS) is visualized in the junction region. This localized ferroelectric polarization induced by illumination enables the heterojunction to exhibit enhanced photoresponsivity. Unlike previous reports that observe multilevel polarization enhancement in electrical resistance, the device shows nonvolatile photoresponsivity enhancement under illumination. After polarization saturation, the photocurrent increases up to 1000 times, from 10-12 to 10-9 A under the irradiation of a 520 nm laser with a power of 1.69 nW, compared to the initial state in a self-driven mode. The photodetector exhibits high detectivity of 4.6×1010 Jones, with a rise time of 27 µs and a fall time of 28 µs. Furthermore, the device's localized poling characteristics and multilevel photoresponse enable spatially multiplexed optical information storage. These results advance the understanding of LIPS in 2D ferroelectric materials, paving the way for optoelectronic information storage technologies.

Construction framework of smart tourism big data mining model driven by blockchain technology.

In the era of sharing economy, the tourism market is increasingly characterized by personalized demand, mobile consumption and product segmentation. This paper aims to apply big data mining technology in the field of smart tourism. Firstly, it focuses on image summary selection and collaborative filtering technology based on big data mining. It then demonstrates the integration of blockchain in smart tourism, emphasizing the use of decentralized structures and smart contracts to achieve data security and transparency, and describes the testing process of smart tourism platforms, including data preparation and platform operational efficiency testing. Finally, the research results of this paper are summarized, and the development potential and practical application value of smart tourism are demonstrated. The results show that in the smart tourism big data mining model, the minimum support for the data set is 10 % and 20 %, respectively. Moreover, with the increase of the number of nodes in the same data set, the running time decreases gradually. It can be seen that smart tourism big data mining has strong scalability.

The Characteristics of Coronary Artery Lesions in COVID-19 Infected Patients With Coronary Artery Disease: An Optical Coherence Tomography Study.

COVID-19 may predispose patients to cardiac injuries but whether COVID-19 infection affects the morphological features of coronary plaques to potentially influence the outcome of patients with coronary artery disease (CAD) remains unknown. By using optical coherence tomography (OCT), this study compared the characteristics of coronary plaque in patients with CAD with/without COVID-19 infection. The 206 patients were divided into 2 groups. The COVID-19 group had 113 patients between December 7, 2022, and March 31, 2023, who received OCT assessment after China decided to lift the restriction on COVID-19 and had a history of COVID-19 infection. The non-COVID-19 group had 93 patients without COVID-19 infection who underwent OCT before December 7, 2022. The COVID-19 group demonstrated a higher incidence of plaque ruptures (53.1% vs 38.7%, p = 0.039), erosions (28.3% vs 11.8%, p = 0.004), fibrous (96.5% vs 89.2%, p = 0.041) and diffuse lesions (73.5% vs 50.5%, p <0.001) compared with the non-COVID-19 group, whereas non-COVID-19 group exhibited a higher frequency of cholesterol crystals (83.9% vs 70.8%, p = 0.027), deep calcifications (65.6% vs 51.3%, p = 0.039) and solitary lesions (57.0% vs 34.5%, p = 0.001). Kaplan-Meier survival analysis revealed a significantly lower major adverse cardiac events-free probability in the COVID-19 group (91.6% vs 95.5%, p = 0.006) than in the non-COVID-19 group. In conclusion, OCT demonstrated that COVID-19 infection is associated with coronary pathological changes such as more plaque ruptures, erosions, fibrosis, and diffuse lesions. Further, COVID-19 infection is associated with a higher propensity for acute coronary events and a higher risk of major adverse cardiac events in patients with CAD.

RNA N6-methyladenosine methylation in influenza A virus infection.

Influenza A virus (IAV) is a negative-sense single-stranded RNA virus that causes acute lung injury and acute respiratory distress syndrome, posing a serious threat to both animal and human health. N6-methyladenosine (m6A), a prevalent and abundant post-transcriptional methylation of RNA in eukaryotes, plays a crucial regulatory role in IAV infection by altering viral RNA and cellular transcripts to affect viral infection and the host immune response. This review focuses on the molecular mechanisms underlying m6A modification and its regulatory function in the context of IAV infection and the host immune response. This will provide a better understanding of virus-host interactions and offer insights into potential anti-IAV strategies.

Sustained chronic inflammation and altered childhood vaccine responses in children exposed to Zika virus.

BACKGROUND: Congenital Zika virus (ZIKV) infection leads to severe newborn abnormalities, but its long-term impact on childhood immunity is not well understood. This study aims to investigate the serum proteomics in children exposed to ZIKV during pregnancy to understand potential immunological consequences during early childhood. METHODS: The study included ZIKV-exposed infants (ZEI) at birth (n = 42) and children exposed to ZIKV (ZEC) at two years of age (n = 20) exposed to ZIKV during pregnancy, as well as healthy controls. Serum proteomic analysis was performed on these groups to assess inflammation and immune profiles. Additionally, antibody titres against two common childhood vaccines, DTaP and MMR, were measured in healthy controls (n = 50) and ZEC (n = 92) to evaluate vaccine-induced immunity. FINDINGS: Results showed elevated inflammation in ZEI with birth abnormalities. Among ZEC, despite most having normal clinical outcomes at two years, their serum proteomics indicated a bias towards Th1-mediated immune responses. Notably, ZEC displayed reduced anti-Diphtheria toxin and anti-Clostridium tetani IgG levels against DTaP and MMR vaccines. They also exhibited lower antibody titres particularly against Th2-biased DTaP vaccines, but not Th1-biased MMR vaccines. INTERPRETATION: In conclusion, the study highlights the long-term immunological consequences of congenital ZIKV exposure. Heightened inflammation was observed in ZEI with abnormalities at birth, while ZEC maintained a chronic Th1-biased immune profile. The impaired response to Th2-biased vaccines raises concerns about lasting effects of ZIKV exposure on immune responses. Consequently, there is a need for continued longitudinal clinical monitoring to identify potential immune-related complications arising from prenatal exposure to ZIKV. FUNDING: This work was partially funded by the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Dental and Craniofacial Research (NIDCR).

Quantum Criticality with Emergent Symmetry in the Extended Shastry-Sutherland Model.

Motivated by the novel phenomena observed in the layered material SrCu_{2}(BO_{3})_{2}, the Shastry-Sutherland model (SSM) has been extensively studied as the minimal model for SrCu_{2}(BO_{3})_{2}. However, the nature of its quantum phase transition from the plaquette valence-bond solid to antiferromagnetic phase is under fierce debate, posing a challenge to understand the underlying quantum criticality. Via the state-of-the-art tensor network simulations, we study the ground state of the SSM on large-scale size up to 20×20 sites. We identify the continuous transition nature accompanied by an emergent O(4) symmetry between the plaquette valence-bond solid and antiferromagnetic phase, which strongly suggests a deconfined quantum critical point (DQCP). Furthermore, we map out the phase diagram of an extended SSM that can be continuously tuned to the SSM, which demonstrates the same DQCP phenomena along a whole critical line. Our results indicate a compelling scenario for understanding the origin of the proposed proximate DQCP in recent experiments of SrCu_{2}(BO_{3})_{2}.

Influence of mandatory waste classification on environmental and economic impacts of residual waste treatment in Xiamen, China.

Mandatory waste classification has been widely considered as an effective solution for reducing the production and treatment amount of municipal solid waste. However, there is limited evidence regarding whether and how waste classification can affect the composition of residual waste (RW) and its environmental economic impacts. Here, an accounting method recommended by the Intergovernmental Panel on Climate Change, field surveys and cost-benefit analysis was utilized to investigate the changes in RW composition, environmental impacts and economic benefits under the waste classification policies implementation in Xiamen, China. This study found that: (1) The implementation of waste classification policies led to a significant increase in recyclable content from 17% to 51% and a decrease in organic content from 56% to 32%. (2) Waste classification effectively reduces greenhouse gas emissions from landfilling and incineration by an additional 0.34 tCO2-eq t-1 RW. (3) The introduction of mechanical recycling achieves a saving of 0.47 tCO2-eq t-1 RW at 40% recycling efficiency, a 4.5-fold increase compared to business as usual (BAU). (4) The operational benefits (900 yuan t-1 RW) from the recyclables sorting system offset the total expenses of investment, operation and waste disposal. The study successfully demonstrated that RW source-classified management can optimize the structure of waste composition, reduce environmental emissions and offer detailed guidance for the development of solid waste management systems in other cities in China.

Coronary microvascular dysfunction and myocardial area at risk assessed by cadmium zinc telluride single photon emission computed tomography after primary percutaneous coronary intervention in acute myocardial infarction patients.

Background: A high proportion of coronary microvascular dysfunction (CMD) has been observed in patients with acute myocardial infarction (AMI) who have received primary percutaneous coronary intervention (PCI), which may affect their prognosis. This study used cadmium zinc telluride (CZT) single photon emission computed tomography (SPECT) to evaluate the prevalence and characteristics of CMD and myocardial area at risk (AAR) in AMI patients who had undergone primary PCI. Methods: We conducted a single-center cross-sectional retrospective study at TEDA International Cardiovascular Hospital from September 2021 to June 2022. A total of 83 patients received primary PCI for AMI. Subsequently, a rest/stress dynamic and routine gated myocardial perfusion imaging (MPI) were performed 1 week after PCI. The CMD group was defined as having a residual stenosis of infarct-related artery (IRA) <50% and myocardial flow reserve (MFR) <2.0 in this corresponding territory, whereas MFR ≥2.0 of IRA pertained to the normal control group. Rest-AAR of infarction (%) and stress-AAR (%) were expressed by the percentage of measured rest-defect-size and stress-defect-size in the left ventricular area, respectively. Logistic regression analyses were performed to identify significant predictors of CMD. Results: A total of 53 patients with a mean age of 57.06±11.99 years were recruited, of whom 81.1% were ST-segment elevation myocardial infarction (STEMI). The proportion of patients with CMD was 79.2% (42/53). The time of pain to SPECT imaging was 7.50±1.27 days in the CMD group and 7.45±1.86 days among controls. CMD patients had a higher body mass index (BMI) than controls (26.48±3.26 vs. 24.36±2.73 kg/m2, P=0.053), and a higher proportion of STEMI, thrombolysis in myocardial infarction (TIMI) 0 grade of IRA prior PCI than controls (88.1% vs. 54.5%, P=0.011; 61.9% vs. 18.2%, P=0.004, respectively). No significant difference was identified in the rest-myocardial blood flow (MBF) of IRA between the 2 groups, whereas the stress-MBF and MFR of IRA, rest-AAR, and stress-AAR in the CMD group were remarkably lowered. Higher BMI [odds ratio (OR): 1.332, 95% confidence interval (CI): 1.008-1.760, P=0.044] and stress-AAR (OR: 1.994, 95% CI: 1.122-3.543, P=0.019) were used as independent predictors of CMD occurrence. Conclusions: The prevalence of CMD is high in AMI patients who received primary PCI. Each 1 kg/m2 increase in BMI was associated with a 1.3-fold increase in CMD risk. A 5% increase in stress-AAR was associated with a nearly 2-fold increase in CMD risk. Increased BMI and stress-AAR predicts decreased coronary reserve function.

Direct, Embedded, and Embodied Trade of Arsenic: 1990-2019.

International arsenic trade, physical and virtual, has resulted in considerable transfer of arsenic pollution across regions. However, no study has systematically captured, estimated, and compared physical and virtual arsenic trade and its relevant impacts. This study combines material flow analysis and embodied emission factors to estimate embedded (including direct and indirect trade) and embodied arsenic trade during 1990-2019, encompassing 18 arsenic-containing products among 244 countries. Global embedded arsenic trade increased considerably from 47 ± 7.3 to 450 ± 68 kilotonnes (kt) during this time and was dominated by indirect arsenic trade, contributing 94 and 90% to global arsenic trade in 1990 and 2019, respectively. Since the 1990s, global arsenic trade centers and the main flows have shifted from European and American markets to developing countries. The mass of arsenic involved in embodied trade increased from 87.5 ± 26 kt in 1990 to 800 ± 236 kt in 2019. Direct trade and indirect trade aggravate arsenic environmental emissions in major importing countries, like China, while embodied trade aggravates arsenic environmental emissions in major exporting countries, like Peru and Chile. The trade-related arsenic pollution transfer calls for a rational arsenic emission responsibility-sharing mechanism and corresponding policy recommendations for different trading countries.

Incorporating platinum circular economy into China's hydrogen pathways toward carbon neutrality.

Hydrogen is gaining tremendous traction in China as the fuel of the future to support the country's carbon neutrality ambition. Despite that hydrogen as fuel largely hinges on the supply of platinum (Pt), the dynamic interlinkage between Pt supply challenges, hydrogen development pathways, and climate targets in China has yet to be deeply analyzed. Here, we adopt an integrated assessment model to address this important concern and corresponding strategies for China. The results indicate that the booming hydrogen development would drive China's cumulative demand for Pt metal to reach 4,200-5,000 tons. Much of this demand, met through a limited supply pattern, is vulnerable to price volatility and heightened geopolitical risks, which can be mitigated through circular economy strategies. Consequently, a coordinated approach to leverage both global sustainable Pt sourcing and a robust domestic Pt circular economy is imperative for ensuring cost-effective hydrogen production, aligned with a climate-safe future.

Mechanical Constraints in Tumor Guide Emergent Spatial Patterns of Glioblastoma Cancer Stem Cells.

The mechanical constraints in the overcrowding glioblastoma (GBM) microenvironment have been implicated in the regulation of tumor heterogeneity and disease progression. Especially, such mechanical cues can alter cellular DNA transcription and give rise to a subpopulation of tumor cells called cancer stem cells (CSCs). These CSCs with stem-like properties are critical drivers of tumorigenesis, metastasis, and treatment resistance. Yet, the biophysical and molecular machinery underlying the emergence of CSCs in tumor remained unexplored. This work employed a two-dimensional micropatterned multicellular model to examine the impact of mechanical constraints arisen from geometric confinement on the emergence and spatial patterning of CSCs in GBM tumor. Our study identified distinct spatial distributions of GBM CSCs in different geometric patterns, where CSCs mostly emerged in the peripheral regions. The spatial pattern of CSCs was found to correspond to the gradients of mechanical stresses resulted from the interplay between the cell-ECM and cell-cell interactions within the confined environment. Further mechanistic study highlighted a Piezo1-RhoA-focal adhesion signaling axis in regulating GBM cell mechanosensing and the subsequent CSC phenotypic transformation. These findings provide new insights into the biophysical origin of the unique spatial pattern of CSCs in GBM tumor and offer potential avenues for targeted therapeutic interventions.

Association between serum creatinine and 30 days all-cause mortality in critically ill patients with non-traumatic subarachnoid hemorrhage: analysis of the MIMIC-IV database.

Background: Serum creatinine is a prognostic marker for various conditions, but its significance of spontaneous subarachnoid hemorrhage is still poorly understood. This study aims to elucidate the correlation between admission serum creatinine (sCr) levels and all-cause mortality within 30 days among individuals affected by non-traumatic subarachnoid hemorrhage (SAH). Methods: This cohort study included 672 non-traumatic SAH adults. It utilized data from the MIMIC-IV database from 2008 to 2019. The patients' first-time serum creatinine was recorded. Subsequently, an examination of the 30-day all-cause mortality was conducted. Employing a multiple logistic regression model, a nomogram was constructed, while the association between sCr and 30-day all-cause mortality was evaluated using Kaplan-Meier survival curves. The calibration curve was employed to assess the model's performance, while subgroup analysis was employed to examine the impact of additional complications and medication therapy on outcomes. Results: A total of 672 patients diagnosed with non-traumatic subarachnoid hemorrhage were included in the study. The mortality rate within this timeframe was found to be 24.7%. Multiple logistic regression analysis revealed that sCr served as an independent prognostic indicator for all-cause mortality within 30 days of admission for SAH patients [OR: 2(1.18-3.41); p = 0.01]. A comprehensive model was constructed, incorporating age, sCr, white blood cell count (WBC), glucose, anion gap, and partial thromboplastin time (PTT), resulting in a prediction model with an AUC value of 0.806 (95% CI: 0.768, 0.843), while the AUC for the test set is 0.821 (95% CI: 0.777-0.865). Conclusion: Creatinine emerges as a significant biomarker, closely associated with heightened in-hospital mortality in individuals suffering from SAH.

The Effect of Dexamethasone on Neuroinflammation and Cerebral Edema in Rats With Traumatic Brain Injury Combined With Seawater Drowning.

OBJECTIVE: To investigate the effect and mechanism of dexamethasone (DX) on axonal injury after traumatic brain injury (TBI) combined with seawater drowning (SWD) in rats. METHODS: To gain an in-depth understanding of TBI + SWD in rats, we established the compound injury model of rats by the Marmarou method and intratracheal pumping of seawater to simulate the pathological conditions. Rats in the DX group received intraperitoneal injections of DX (1 mg/kg) immediately after injury, and rats in the sham group and TBI + SWD group received intraperitoneal injections of the same amount of normal saline. RESULTS: Hematoxylin-eosin (HE) showed that DX improved matrix looseness, cell swelling, and nuclear condensation 168 hours after injury. Immunohistochemistry (IHC) staining showed that the protein expression of AQP4 was decreased in the DX group compared with the TBI + SWD group from 12 hours to 168 hours after injury. DX decreased the modified neurological severity score (mNSS) significantly at 24 hours and 168 hours after injury (P < 0.05). At 72 h and 168 h after injury, DX significantly lowered the expressions of IL-8 and TNF-α (P < 0.05). CONCLUSION: DX may play a neuroprotective role by reducing cerebral edema and inflammatory response after TBI + SWD injury in rats.

Electrochemical coalescence of oil-in-water droplets in microchannels of TiO2-x/Ti anode via polarization eliminating electrostatic repulsion and ·OH oxidation destroying oil-water interface film.

Electrochemistry is a sustainable technology for oil-water separation. In the common flat electrode scheme, due to a few centimeters away from the anode, oil droplets have to undergo electromigration to and electrical neutralization at the anodic surface before they coalesce into large oil droplets and rise to water surface, resulting in slow demulsification and easy anode fouling. Herein, a novel strategy is proposed on basis of a TiO2-x/Ti anode with microchannels to overcome these problems. When oil droplets with several microns in diameter flow through channels with tens of microns in diameter, the electromigration distance is shortened by three orders of magnitude, electrical neutralization is replaced by polarization coupling ·OH oxidation. The new strategy was supported by experimental results and theoretical analysis. Taking the suspension containing emulsified oil as targets, COD value dropped from initial 500 mg/L to 117 mg/L after flowing through anodic microchannels in only 58 s of running time, and the COD removal was 21 times higher than that for a plate anode. At similar COD removal, the residence time was 48 times shorter than that of reported flat electrodes. Coalescences of oil droplets in microchannels were observed by a confocal laser scanning microscopy. This new strategy opens a door for using microchannel electrodes to accelerate electrochemical coalescence of oil-in-water droplets.

Elevated Circulating Procathepsin L as a Potential Biomarker of Inflamm-aging.

Inflamm-aging is a condition of low-grade and chronic systemic inflammation characterized by a systemic increase in multiple inflammatory biomarkers such as tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), and CXCL9 (MIG) in experimental and clinical settings. However, despite the recent identification of extracellular procathepsin L (pCTS-L) as a novel mediator of inflammatory diseases such as sepsis, its possible role in inflamm-aging was previously not investigated. In the present study, we compared blood levels of pCTS-L and other 62 cytokines and chemokines between young and aged Balb/C mice by Western blotting and Cytokine Antibody Arrays. In light of the surprising finding of a marked increase in blood pCTS-L levels in aged mice, we propose that blood pCTS-L levels may serve as another biomarker of inflamm-aging. Given the capacity of pCTS-L in inducing various cytokines (e.g., TNF and IL-6), it will be important to test the hypothetic role of pCTS-L in inflamm-aging under experimental and clinical conditions.

The feasibility of the posterior tibial nerve-flexor hallucis brevis pathway applied in neuromuscular monitoring: a multicentric, controlled, and prospective clinical trial.

This study aimed to investigate the clinical viability of utilizing the flexor hallucis brevis as an alternative site for neuromuscular monitoring compared to the conventional adductor pollicis. Patients were recruited from three medical centers. Cis-atracurium was administered, and two monitors were employed independently to assess neuromuscular blockade of the adductor pollicis and the ipsilateral flexor hallucis brevis, following a train of four (TOF) pattern until TOF ratios exceeded 0.9 or until the conclusion of surgery. Statistical analysis revealed significant differences in onset time, duration of no-twitch response, spontaneous recovery time, and total monitoring time between the two sites, with mean differences of -53.54 s, -2.49, 3.22, and 5.89 min, respectively (P < 0.001).The posterior tibial nerve-flexor hallucis brevis pathway presents a promising alternative for neuromuscular monitoring during anesthesia maintenance. Further investigation is warranted to explore its utility in anesthesia induction and recovery. Trial registration: The trial was registered at www.chictr.org.cn (20/11/2018, ChiCTR1800019651).

Liquiritin Carbomer Gel Cold Paste Promotes Healing of Solar Dermatitis in Mice.

Ultraviolet radiation (UVR) has various effects on human cells and tissues, which can lead to a variety of skin diseases and cause inconvenience to people's lives. Among them, solar dermatitis is one of the important risk factors for malignant melanoma, so prevention and treatment of solar dermatitis is very necessary. Additionally, liquiritin (LQ) has anti-inflammatory effects. In this study, we aimed to evaluate the anti-inflammatory and pro-wound healing effects of liquiritin carbomer gel cold paste (LQ-CG-CP) in vitro and in vivo. The results of MTT experiments showed no cytotoxicity of LQ at concentrations of 40 µg/mL and below and cell damage at UVB irradiation doses above 60 mJ/cm2. Moreover, LQ can promote cell migration. ELISA results also showed that LQ inhibited the elevation of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after UVB irradiation. In the mouse model of solar dermatitis, 2% LQ-CG-CP showed the best therapeutic efficacy for wound healing and relief of itching compared to MEIBAO moist burn moisturizer (MEBO). What is more, the results of skin histopathological examination show that LQ-CG-CP promotes re-epithelialization, shrinks wounds, and promotes collagen production, thus promoting wound healing. Simultaneously, LQ-CG-CP reduced TNF-α, IL-1ß, and IL-6 expression. In addition, LQ-CG-CP was not observed to cause histopathological changes and blood biochemical abnormalities in mice. Overall, LQ-CG-CP has great potential for the treatment of solar dermatitis.

Analgesia nociception index is an indicator of laparoscopic trocar insertion-induced transient nociceptive stimuli.

Objective: This study aimed to investigate whether analgesia nociception index (ANI) could be an indicator of perioperative pain during laparoscopic trocar insertion. Methods: A total of 280 participants of anesthesia receiving laparoscopic surgery were enrolled. Anesthesia induction and maintenance were performed using the Marsh model for target propofol and the Minto model for remifentanil. Systolic blood pressure (SBP), heart rate (HR), and ANI were recorded at skin incision, the first-, second, the last-trocar insertion, and 5 min after the last trocar insertion. Results: ANI was significantly different among the five groups in the last four time points (all P < 0.05). Pearson's correlation showed that ANI was negatively correlated with SBP (r = -0.114, P = 0.077) and HR (r = -0.247, P < 0.001). The area under the curve of ANI was positively correlated with those of SBP (r = 0.493, P < 0.001) and HR (r = -0.420, P < 0.001). Multivariate logistic regression showed that the ANI was an independent factor associated with intraoperative hemodynamic adverse events only at 5 min after the last trocar insertion. Conclusions: Under general anesthesia, the change in ANI was consistent with changes in the balance between analgesia and nociceptive stimuli. The ANI can reflect the extent of transient pain but had a poor predictive performance for hemodynamic adverse events.

Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-ß-cyclodextrin nanoparticles in treating experimental sepsis.

The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S. Drug Collection could suppress pCTS-L-induced inflammation, and pharmacologically be exploited into possible therapies. Here, we demonstrated that a macrophage cell-based screening of a U.S. Drug Collection of 1360 compounds resulted in the identification of progesterone (PRO) as an inhibitor of pCTS-L-mediated production of several chemokines [e.g., Epithelial Neutrophil-Activating Peptide (ENA-78), Monocyte Chemoattractant Protein-1 (MCP-1) or MCP-3] and cytokines [e.g., Interleukin-10 (IL-10) or Tumor Necrosis Factor (TNF)] in primary human peripheral blood mononuclear cells (PBMCs). In vivo, these PRO-entrapping 2,6-dimethal-ß-cyclodextrin (DM-ß-CD) nanoparticles (containing 1.35 mg/kg PRO and 14.65 mg/kg DM-ß-CD) significantly increased animal survival in both male (from 30% to 70%, n = 20, P = 0.041) and female (from 50% to 80%, n = 30, P = 0.026) mice even when they were initially administered at 24 h post the onset of sepsis. This protective effect was associated with a reduction of sepsis-triggered accumulation of three surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF) by 40%; Macrophage Inflammatory Protein-2 (MIP-2) by 45%; and Soluble Tumor Necrosis Factor Receptor I (sTNFRI) by 80%]. Surface Plasmon Resonance (SPR) analysis revealed a strong interaction between PRO and pCTS-L (KD = 78.2 ± 33.7 nM), which was paralleled with a positive correlation between serum PRO concentration and serum pCTS-L level (ρ = 0.56, P = 0.0009) or disease severity (Sequential Organ Failure Assessment, SOFA; ρ = 0.64, P = 0.0001) score in septic patients. Our observations support a promising opportunity to explore DM-ß-CD nanoparticles entrapping lipophilic drugs as possible therapies for clinical sepsis.