Phage cocktail superimposed disinfection: A ecological strategy for preventing pathogenic bacterial infections in dairy farms.

Bovine mastitis (BM) is mainly caused by bacterial infection that has a highly impact on dairy production, affecting both economic viability and animal well-being. A cross-sectional study was conducted in dairy farms to investigate the prevalence and antimicrobial resistance patterns of bacterial pathogens associated with BM. The analysis revealed that Staphylococcus (49%), Escherichia (16%), Pseudomonas (11%), and Klebsiella (6%) were the primary bacterial pathogens associated with mastitis. A significant proportion of Staphylococcus strains displayed multiple drug resistance. The use of disinfectants is an important conventional measure to control the pathogenic bacteria in the environment. Bacteriophages (Phages), possessing antibacterial properties, are natural green and effective disinfectants. Moreover, they mitigate the risk of generating harmful disinfection byproducts, which are commonly associated with traditional disinfection methods. Based on the primary bacterial pathogens associated with mastitis in the investigation area, a phage cocktail, named SPBC-SJ, containing seven phages capable of lysing S. aureus, E. coli, and P. aeruginosa was formulated. SPBC-SJ exhibited superior bactericidal activity and catharsis effect on pollutants (glass surface) compared to chemical disinfectants. Clinical trials confirmed that the SPBC-SJ-based superimposed disinfection group (phage combined with chemical disinfectants) not only cut down the dosage of disinfectants used, but significantly reduced total bacterial counts on the ground and in the feeding trough of dairy farms. Furthermore, SPBC-SJ significantly reduced the abundance of Staphylococcus and Pseudomonas in the environment of the dairy farm. These findings suggest that phage-based superimposed disinfection is a promising alternative method to combat mastitis pathogens in dairy farms due to its highly efficient and environmentally-friendly properties.

Shape-Selective Alkylation of Toluene with Ethanol over a Twin Intergrowth Structured ZSM-5: Modulation of Acidity and Diffusivity via Interface Engineering.

ZSM-5 zeolites with modified acidity and diffusivity are employed as catalysts for the shape-selective alkylation of toluene with ethanol to para-ethyltoluene (p-ET). To avoid pore blocking and loss of active sites caused by traditional methods of enhancing para-selectivity using modifiers, here, we constructed twin intergrowth structured ZSM-5 (Z5-T), achieving modulation of the inherent acidity and diffusivity through interface engineering. The characterization results demonstrate that due to the intergrowth interface, the Z5-T catalyst forms more inherent Lewis acid sites and also renders more sinusoidal channels opened to the surface. Z5-T with an appropriate acidity and enhanced shape-selectivity inhibits side reactions such as isomerization and coke formation, demonstrating improved p-ET selectivity (>90%) and catalytic stability (>200 h) in the alkylation of toluene with ethanol.

HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.

Isoflurane, a widely used inhalation anesthetic in clinical practice, is associated with an increased risk of neuronal injury. Heat shock protein 90 (HSP90) plays a crucial role in maintaining neuronal homeostasis under stress conditions; however, its role during isoflurane exposure remains poorly understood. In this study, we aimed to investigate the protective effects of HSP90 inhibition and explore the regulatory mechanisms underlying these effects during isoflurane exposure. We found that the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17 AAG) has great protective effects in mitigating isoflurane-induced ferroptosis of mouse hippocampus and cultured neuronal cells. We focused on the activity of the crucial protein GPX4 in ferroptosis and found that 17 AAG exerted protective effects, preserving the physiological GPX4 activity under isoflurane exposure; further, 17 AAG restored the protein level of GPX4. Further, we observed that the chaperone-mediated autophagy (CMA) pathway was activated; 17 AAG also mediated GPX4 degradation under isoflurane exposure. Additionally, it interfered with the formation of complexes between HSP90 and Lamp-2a, inhibiting CMA activity, followed by the blockade of GPX4 degradation, further affecting the isoflurane-induced ferroptosis. Based on these findings, we proposed HSP90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.

Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.

Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.NEW & NOTEWORTHY This article discusses the effects and mechanisms of Parkin-mediated mitophagy in oxaliplatin-induced peripheral nerve pain (OIPNP) from both in vivo and in vitro. We believe that our study makes a significant contribution to the literature because OIPNP has always been the focus of clinical medicine, and mitochondrial quality regulation mechanisms especially Parkin-mediated mitophagy, have been deeply studied in recent years. We use a variety of molecular biological techniques and animal experiments to support our argument.

Efficacy and safety of CM310 in moderate-to-severe atopic dermatitis: A multicenter, randomized, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied. RESULTS: At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs . placebo, 95% CI 31%-69%) and 45% (low vs . placebo, 95% CI 26%-64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator's Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. CONCLUSION: CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.

Searching High-Potential Dihydroxynaphthalene Cathode for Rocking-Chair All-Organic Aqueous Proton Batteries.

The lack of acid-proof high-potential cathode largely limits the development and competitiveness of proton batteries. Herein, the authors systematically investigated six dihydroxynaphthalenes (DHNs) and found that 2,6-DHN delivered the best cathode performance in proton battery with the highest redox potential (0.84 V, vs SHE) and a specific capacity of 91.6 mAh g-1 at 1 A g-1 . In situ solid-state electropolymerization of DHNs is responsible for the voltage and capacity fading of DHNs, and 2,6-DHN's excellent electrochemical performance is derived from its high polymerization energy barrier. By compounding with rGO, the 2,6-DHN/rGO electrode can maintain a specific capacity of 89 mAh g-1 even after 12 000 cycles at 5 A g-1 . When it is paired with the 2,6-dihydroxyanthraquinone (DHAQ) anode, the assembled rocking-chair all-organic proton battery exhibited a high cell voltage of 0.85 V, and excellent energy/power densities (70.8 Wh kg-1 /850 W kg-1 ). This study showcases a new-type high-potential proton-containing organic cathode and paves the way for constructing a high-voltage rocking-chair proton battery. Also, in situ solid-state electropolymerization will inspire the further study of phenol-based small-molecule electrodes.

Leveraging Temporal Wnt Signal for Efficient Differentiation of Intestinal Stem Cells in an Organoid Model.

The homeostasis of the intestinal epithelium heavily relies on the self-renewal and differentiation of intestinal stem cells (ISCs). Although the orchestration of these processes by signaling pathways such as the Wnt, BMP, Notch, and MAPK signals has been extensively studied, the dynamics of their regulation remains unclear. Our study explores how the Wnt signaling pathway temporally regulates the differentiation of ISCs into various cell types in an intestinal organoid system. We report that the duration of Wnt exposure following Notch pathway inactivation significantly influences the differentiation direction of intestinal epithelial cells toward multiple secretory cell types, including goblet cells, enteroendocrine cells (EECs), and Paneth cells. This temporal regulation of Wnt signaling adds another layer of complexity to the combination of niche signals that govern cell fate. By manipulating this temporal signal, we have developed optimized protocols for the efficient in vitro differentiation of ISCs into EECs and goblet cells. These findings provide critical insights into the dynamic regulation of ISC differentiation and offer a robust platform for future investigations into intestinal biology and potential therapeutic applications.

PVDF-HFP via Localized Iodization as Interface Layer for All-Solid-State Lithium Batteries with Li6 PS5 Cl Films.

All-solid lithium (Li) metal batteries (ASSLBs) with sulfide-based solid electrolyte (SEs) films exhibit excellent electrochemical performance, rendering them capable of satisfying the growing demand for energy storage systems. However, challenges persist in the application of SEs film owing to their reactivity with Li metal and uncontrolled formation of lithium dendrites. In this study, iodine-doped poly(vinylidenefluoride-hexafluoropropylene) (PVDF-HFP) as an interlayer (PHI) to establish a stable interphase between Li metal and Li6 PS5 Cl (LPSCl) films is investigated. The release of I ions and PVDF-HFP produces LiI and LiF, effectively suppressing lithium dendrite growth. Density functional theory calculations show that the synthesized interlayer layer exhibits high interfacial energy. Results show that the PHI@Li/LPSCl film/PHI@Li symmetrical cells can cycle for more than 650 h at 0.1 mA cm-2 . The PHI@Li/LPSCl film/NCM622 cell exhibits a distinct enhancement in capacity retention of ≈26% when using LiNi0.6 Mn0.2 Co0.2 O2 (NCM622) as the cathode, compared to pristine Li metal as the anode. This study presents a feasible method for producing next-generation dendrite-free SEs films, promoting their practical use in ASSLBs.

HOMER3 promotes non-small cell lung cancer growth and metastasis primarily through GABPB1-mediated mitochondrial metabolism.

Cancer metabolism has emerged as a major target for cancer therapy, while the state of mitochondrial drugs has remained largely unexplored, partly due to an inadequate understanding of various mitochondrial functions in tumor contexts. Here, we report that HOMER3 is highly expressed in non-small cell lung cancer (NSCLC) and is closely correlated with poor prognosis. Lung cancer cells with low levels of HOMER3 are found to show significant mitochondrial dysfunction, thereby suppressing their proliferation and metastasis in vivo and in vitro. At the mechanistic level, we demonstrate that HOMER3 and platelet-activating factor acetylhydrolase 1b catalytic subunit 3 cooperate to upregulate the level of GA-binding protein subunit beta-1 (GABPB1), a key transcription factor involved in mitochondrial biogenesis, to control mitochondrial inner membrane genes and mitochondrial function. Concurrently, low levels of HOMER3 and its downstream target GABPB1 led to mitochondrial dysfunction and decreased proliferation and invasive activity of lung cancer cells, which raises the possibility that targeting mitochondrial synthesis is an important and promising therapeutic approach for NSCLC.

Postoperative stellate ganglion block to reduce myocardial injury after laparoscopic radical resection for colorectal cancer: protocol for a randomised trial.

INTRODUCTION: Stellate ganglion block (SGB) is usually used in the department of algiatry. But preoperative SGB may reduce adverse cardiovascular events in high-risk patients, although evidence remains sparse. Therefore, we aim to determine whether a single-shot postoperative SGB can reduce the incidence of myocardial injury after non-cardiac surgery (MINS) and improve recovery in patients undergoing laparoscopic radical resection for colorectal cancer. METHODS AND ANALYSIS: This is an investigator-initiated, single-centre, randomised, two-arm clinical trial enrolling patients aged over 45 years and scheduled for elective laparoscopic radical colorectal surgery with at least one risk factor for MINS. A total of 950 eligible patients will be randomised into a routine or block groups. The primary outcome is the incidence of MINS. The secondary outcomes include the Visual Analogue Scale of pain during rest and movement, the incidence of delirium, quality of recovery (QOR) assessed by QOR-15, and sleep quality assessed by Richards Campbell Sleep Questionnaire. Tertiary outcomes include time to first flatus, gastrointestinal complications such as anastomotic leak or ileus, length of hospital stay, collapse incidence of severe cardiovascular and cerebrovascular complications of myocardial infarction, cardiac arrest, ischaemic or haemorrhagic stroke, and all-cause mortality within 30 days after the operation. ETHICS AND DISSEMINATION: The protocol was approved by Medical Ethics Committee of the China-Japan Union Hospital, Jilin University (Approval number: 2021081018) prior to recruitment. The study will be performed according to the guidelines of the Declaration of Helsinki. The findings of this study will be published and presented through various scientific forums. TRIAL REGISTRATION NUMBER: ChiCTR2200055319.

Programmable and Reversible Integrin-Mediated Cell Adhesion Reveals Hysteresis in Actin Kinetics that Alters Subsequent Mechanotransduction.

Dynamically evolving adhesions between cells and extracellular matrix (ECM) transmit time-varying signals that control cytoskeletal dynamics and cell fate. Dynamic cell adhesion and ECM stiffness regulate cellular mechanosensing cooperatively, but it has not previously been possible to characterize their individual effects because of challenges with controlling these factors independently. Therefore, a DNA-driven molecular system is developed wherein the integrin-binding ligand RGD can be reversibly presented and removed to achieve cyclic cell attachment/detachment on substrates of defined stiffness. Using this culture system, it is discovered that cyclic adhesion accelerates F-actin kinetics and nuclear mechanosensing in human mesenchymal stem cells (hMSCs), with the result that hysteresis can completely change how hMSCs transduce ECM stiffness. Results are dramatically different from well-known results for mechanotransduction on static substrates, but are consistent with a mathematical model of F-actin fragments retaining structure following loss of integrin ligation and participating in subsequent repolymerization. These findings suggest that cyclic integrin-mediated adhesion alters the mechanosensing of ECM stiffness by hMSCs through transient, hysteretic memory that is stored in F-actin.

A quasi-experimental study of fresh oxygen flow on patients' oxygen reserve during mask-assisted ventilation under general anesthesia induction.

Background: To compare the effect of different amounts of fresh oxygen flow on oxygen reserve in patients undergoing general anesthesia. Methods: Seventy-two patients were enrolled in this quasi-experimental study. Patients were randomly divided into experimental groups with a fresh oxygen flow of 1 L/min, 2 L/min, 4 L/min, and 8 L/min (denoted as G1, G2, G3, and G4, respectively) for 2 min of mask-assisted ventilation. Safe apnea time (SAT) was the primary endpoint; SAT was defined as the time from the cessation of ventilation to the time the patient's pulse oxygen saturation (SpO2) decreased to 90%. Ventilation indicators such as end-tidal oxygen concentration (EtO2), end-tidal carbon dioxide partial pressure (EtCO2), SpO2, and carbon dioxide (CO2) elimination amount, during mask-assisted ventilation, were the secondary endpoints. Results: The SAT of G1, G2, G3, and G4 were 305.1 ± 97.0 s, 315 ± 112.5 s, 381.3 ± 118.6 s, and 359 ± 104.4 s, respectively (p > 0.05). The EtO2 after 2 min of mask-assisted ventilation in groups G1, G2, G3, and G4 were 69.7 ± 8.8%, 75.2 ± 5.0%, 82.5 ± 3.3%, and 86.8 ± 1.5%, respectively (p < 0.05). Also, there was a moderate positive correlation between the fresh oxygen flow and EtO2 (correlation coefficient r = 0.52, 95% CI 0.31-0.67, p < 0.0001). The CO2 elimination in the G1 and G2 groups was greater than that in the G4 group (p < 0.05). There was no significant difference in other indicators among the groups (all p > 0.05). Conclusion: The amount of fresh oxygen flow during mask-assisted ventilation was positively correlated with EtO2. Also, even though there was no significant difference, the patients' oxygen reserves increased with the increase in fresh oxygen flow.

Analgesic effects of perioperative acupuncture methods: A narrative review.

Postoperative pain occurs immediately after surgery. The most common perioperative analgesic methods are nerve block, patient-controlled intravenous analgesia, and patient-controlled epidural analgesia. However, overuse of opioid analgesics can cause many adverse reactions including excessive sedation, respiratory inhibition, postoperative nausea, and vomiting. In recent years, many clinical trials have shown that perioperative acupuncture has unique advantages in patients. Perioperative acupuncture can relieve intraoperative pain, improve postoperative pain management, reduce postoperative nausea and vomiting, and shorten the length of hospital stay. This study aimed to confirm the analgesic effect of perioperative acupuncture by reviewing studies on the different methods of perioperative acupuncture and their analgesic effects. The cited literature was searched in English and Chinese from PubMed, China National Knowledge Infrastructure, and Wanfang data, using the following keywords: "perioperative pain," "acupuncture," "electroacupuncture," and "perioperative analgesia." Studies published from 2005 to 2023 were included. All retrieved papers were read in detail. Perioperative acupuncture has benefits in reducing postoperative pain and opioid need. Although analgesic drugs are still the primary means of postoperative pain control, acupuncture provides a safe analgesic supplement or alternative. This review aimed to assist practitioners in choosing appropriate perioperative acupuncture methods by summarizing the recent literature on the role of different acupuncture approaches for perioperative pain management.

Spatial coherence length and wave structure function for plane waves transmitted in anisotropic turbulent oceans.

The spatial coherence length and wave phase structure function are two important factors in describing turbulence's effect on light propagation in seawater. This paper derives the wave phase structure function and spatial coherence length of plane waves in moderate to strong turbulent channels by deriving a "modification seawater turbulence power spectrum" and an oceanic-modified Rytov approximation. The evolutions in wave structure function, coherence length with the temperature dissipation rate, energy dissipation rate, anisotropy turbulence factor, signal wavelength, and propagation distance are analyzed by numerical calculation. In the moderate and strong turbulence regions, the phase structure function and spatial coherence length increase and decrease with increasing transmission distance and turbulence strength, respectively, and there is a saturation tendency for both. The fluctuation of seawater salinity has a greater effect on the phase structure function and coherence length than the temperature fluctuation. In addition, the wave structure function decreases with increasing signal wavelength and degree of turbulent anisotropy, but the trend of spatial coherence length is reversed.

The Effect of Continuing Nursing Intervention on Peritoneal Dialysis Patients and the Occurrence of Peritonitis: A Meta-Analysis.

Background: Chronic kidney disease, affecting millions globally, has emerged as a significant health concern alongside tumors, diabetes, and cardiovascular diseases. Peritoneal dialysis is a widely used therapeutic intervention, but its effectiveness can be compromised by complications such as peritonitis. Methods: We conducted a comprehensive search across eight international databases to obtain controlled trials evaluating the impact of continuous nursing on peritonitis occurrence in peritoneal dialysis patients. Following stringent quality assessment, data analysis was performed using RevMan 5.3 software. Results: Our meta-analysis included 15 controlled trials. Of these, 13 reported peritonitis rates in both intervention and control groups. Continuous nursing was associated with a significant reduction in peritonitis incidence (OR: 0.32; 95% CI: 0.23,0.44) and complications (SMD: 3.21; 95% CI: 1.17,5.25; P = .01), as well as a decrease in serum creatinine levels (SMD: -130.06; 95% CI: -195.46,-64). Conclusion: The findings of this study support the possibility that ongoing nursing is beneficial for the complications and creatinine for peritoneal dialysis patients.

T Cell engineering for cancer immunotherapy by manipulating mechanosensitive force-bearing receptors.

T cell immune responses are critical for in both physiological and pathological processes. While biochemical cues are important, mechanical cues arising from the microenvironment have also been found to act a significant role in regulating various T cell immune responses, including activation, cytokine production, metabolism, proliferation, and migration. The immune synapse contains force-sensitive receptors that convert these mechanical cues into biochemical signals. This phenomenon is accepted in the emerging research field of immunomechanobiology. In this review, we provide insights into immunomechanobiology, with a specific focus on how mechanosensitive receptors are bound and triggered, and ultimately resulting T cell immune responses.

Characterization of the Heat Shock Transcription Factor Family in Medicago sativa L. and Its Potential Roles in Response to Abiotic Stresses.

Heat shock transcription factors (HSFs) are important regulatory factors in plant stress responses to various biotic and abiotic stresses and play important roles in growth and development. The HSF gene family has been systematically identified and analyzed in many plants but it is not in the tetraploid alfalfa genome. We detected 104 HSF genes (MsHSFs) in the tetraploid alfalfa genome ("Xinjiangdaye" reference genome) and classified them into three subgroups: 68 in HSFA, 35 in HSFB and 1 in HSFC subgroups. Basic bioinformatics analysis, including genome location, protein sequence length, protein molecular weight and conserved motif identification, was conducted. Gene expression analysis revealed tissue-specific expression for 13 MsHSFs and tissue-wide expression for 28 MsHSFs. Based on transcriptomic data analysis, 21, 11 and 27 MsHSFs responded to drought stress, cold stress and salt stress, respectively, with seven responding to all three. According to RT-PCR, MsHSF27/33 expression gradually increased with cold, salt and drought stress condition duration; MsHSF6 expression increased over time under salt and drought stress conditions but decreased under cold stress. Our results provide key information for further functional analysis of MsHSFs and for genetic improvement of stress resistance in alfalfa.

Blocking Th2 Signaling Pathway Alleviates the Clinical Symptoms and Inflammation in Allergic Conjunctivitis.

Purpose: To explore the role of Th2 signaling pathway in allergic conjunctivitis (AC). Methods: Serum Th2 cytokines IL-4 or IL-13 of patients with AC were detected using the Meso scale discovery assay to verify the correlation of Th2 immunity and AC pathogenesis. Wistar Han rats were intraperitoneally and subcutaneously injected with ovalbumin (OVA) to establish an experimental AC model and the Th2 signaling pathway was blocked by an investigational neutralizing antibody (CM310). Serum IgE and OVA-specific IgE were detected by ELISA. Conjunctivitis inflammation, infiltration of eosinophils, and mast cell degranulation were detected by histological examination. Immortalized human conjunctival epithelial cells, a conjunctival epithelial cell line, and peripheral blood mononuclear cells of patients with AC were used as the target cells to study the impact of IL-4 or IL-13 on AC progression. Finally, a STAT6 reporter gene system was constructed using immortalized human conjunctival epithelial cells to confirm whether the downstream signaling pathway activated by IL-4 or IL-13. Results: Serum IL-4 or IL-13 were increased in patients with AC versus healthy individuals. In an OVA-induced rat experimental AC model, blocking the Th2 signaling pathway with CM310, an investigational neutralizing antibody, alleviated the conjunctival symptoms, and decreased serum IgE, suppressed infiltration of eosinophils and mast cell degranulation. Further, an in vitro model showed CM310 suppressed the secretion of inflammatory cytokine from both immune cells and epithelial cells in both patients peripheral blood mononuclear cells and cell line. Conclusions: Blocking Th2 signaling pathway alleviates the clinical symptoms and inflammation in AC.

Novel Mechanisms of Perioperative Neurocognitive Disorders: Ferroptosis and Pyroptosis.

Perioperative neurocognitive disorders (PNDs) are some of the most common postoperative complications among the elderly and susceptible individuals, which significantly worsens the clinical outcome of patients. However, the prevention and treatment strategies of PNDs are difficult to determine and implement since the pathogenesis of PNDs is not well understood. The development of living organisms is associated with active and organized cell death, which is essential for maintaining the homeostasis of life. Ferroptosis is a programmed cell death (different from apoptosis and necrosis) mainly caused by an imbalance in the generation and degradation of intracellular lipid peroxides due to iron overload. Pyroptosis is an inflammatory cell death characterized by the creation of membrane holes mediated by the gasdermin (GSDM) family, followed by cell lysis and the release of pro-inflammatory cytokines. Ferroptosis and pyroptosis are involved in the pathogenesis of various central nervous system (CNS) diseases. Furthermore, ferroptosis and pyroptosis are closely associated with the occurrence and development of PNDs. This review summarizes the main regulatory mechanisms of ferroptosis and pyroptosis and the latest related to PNDs. Based on the available evidence, potential intervention strategies that can alleviate PNDs by inhibiting ferroptosis and pyroptosis have also been provided.

Development of a Universal Multi-Epitope Vaccine Candidate against Streptococcus suis Infections Using Immunoinformatics Approaches.

Streptococcus suis is a significant zoonotic pathogen that is a great threat not only to the swine industry but also to human health, causing arthritis, meningitis, and even streptococcal toxic shock-like syndrome. Owing to its many serotypes and high geographic variability, an efficacious cross-protective S. suis vaccine is not readily available. Therefore, this study aimed to design a universal multi-epitope vaccine (MVHP6) that involved three highly immunogenic proteins of S. suis, namely, the surface antigen containing a glycosaminoglycan binding domain (HP0197), endopeptidase (PepO), and 6-phosphogluconate dehydrogenase (6PGD). Forecasted T-cell and B-cell epitopes with high antigenic properties and a suitable adjuvant were linked to construct a multi-epitope vaccine. In silico analysis showed that the selected epitopes were conserved in highly susceptible serotypes for humans. Thereafter, we evaluated the different parameters of MVHP6 and showed that MVHP6 was highly antigenic, non-toxic, and non-allergenic. To verify whether the vaccine could display appropriate epitopes and maintain high stability, the MVHP6 tertiary structure was modeled, refined, and validated. Molecular docking studies revealed a strong binding interaction between the vaccine and the toll-like receptor (TLR4), whereas molecular dynamics simulations demonstrated the vaccine's compatibility, binding stability, and structural compactness. Moreover, the in silico analysis showed that MVHP6 could evoke strong immune responses and enable worldwide population coverage. Moreover, MVHP6 was cloned into the pET28a (+) vector in silico to ensure the credibility, validation, and proper expression of the vaccine construct. The findings suggested that the proposed multi-epitope vaccine can provide cross-protection against S. suis infections.