Structural basis of µ-opioid receptor targeting by a nanobody antagonist.

The µ-opioid receptor (µOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of µOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, represent alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the µOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded µOR ligand and uncover the molecular basis for µOR antagonism by determining the cryo-EM structure of the NbE-µOR complex. NbE displays a unique ligand binding mode and achieves µOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a ß-hairpin loop formed by NbE that deeply protrudes into the µOR, we design linear and cyclic peptide analogs that recapitulate NbE's antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes lower molecular weight µOR ligands that can serve as a basis for therapeutic developments.

Fluoroamphiphiles for enhancing immune response of subunit vaccine against SARS-CoV-2.

In recent decades, protein-based therapy has garnered valid attention for treating infectious diseases, genetic disorders, cancer, and other clinical requirements. However, preserving protein-based drugs against degradation and denaturation during processing, storage, and delivery poses a formidable challenge. Herein, we designed a novel fluoroamphiphiles polymer to deliver protein. Two different formulations of nanoparticles, cross-linked (CNP) and micelle (MNP) polymer, were prepared rationally by disulfide cross-linked and thin-film hydration techniques, respectively. The size, zeta potential, and morphology of both formulations were characterized and the delivery efficacy of both in vitro and in vivo was also assessed. The in vitro findings demonstrated that both formulations effectively facilitated protein delivery into various cell lines. Moreover, in vivo experiments revealed that intramuscular administration of the two formulations loaded with a SARS-CoV-2 recombinant receptor-binding domain (RBD) vaccine induced robust antibody responses in mice without adding another adjuvant. These results highlight the potential use of our carrier system as a safe and effective platform for the in vivo delivery of subunit vaccines.

Analysis of clinical application effects of Esketamine combining Sufentanil in labor analgesia and their impacts on postpartum depression.

Objective: To evaluate the clinical effects of Esketamine combining Sufentanil in labor analgesia and their impacts on postpartum depression. Methods: This was a retrospective study. One hundred and fifty primiparae with spontaneous labor were selected at SSL Central Hospital of Dongguan City from July 10, 2021 to May 10, 2022 as the research objects and randomly divided into two groups (each n=75). While the control group underwent epidural infusion of Sufentanil for analgesia, the study group was administered Esketamine combining Sufentanil. Compared analgesic effects, time of birth course, adverse reactions, pain intensity, scores assigned to depression and anxiety before analgesia and after delivery were made for pregnant women in both groups. Results: The response rates of the study and control groups reached 100% and 93%, respectively, with statistically significant differences (p=0.02). The time of the first, second, and third stages of labor in the study group were all significantly lower than that of the control group; showing statistical significance (p=0.00). Regarding adverse reactions showed no statistically significant differences (p=0.44). Moreover, the study group showed noticeably lower pain intensity than those of the control group during delivery, 20 minutes and one hour after delivery; and their differences were statistically significant (p=0.00). After delivery, both the SAS and SDS of the study group were respectively lower than those of the control group, with statistically significant differences as well (p=0.00). Conclusions: Applying Esketamine combining Sufentanil in epidural painless delivery produces rather favorable analgesic effects, shortens the time of the birth process, and improves postpartum anxiety and depression without leading to more adverse reactions.

Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule-Binding Domain and Enhances Liquid-Liquid Phase Separation of Tau.

Liquid-liquid phase separation (LLPS) of tau protein can initiate its aggregation which is associated with Alzheimer's disease. The pathogenic mutation ΔK280 can enhance the aggregation of K18, a truncated tau variant comprising the microtubule-binding domain. However, the impact of ΔK280 on K18 LLPS and underlying mechanisms are largely unexplored. Herein, the conformational ensemble and LLPS of ΔK280 K18 through multiscale molecular simulations and microscopy experiments are investigated. All-atom molecular dynamic simulations reveal that ΔK280 significantly enhances the collapse degree and ß-sheet content of the K18 monomer, indicating that ΔK280 mutation may promote K18 LLPS, validated by coarse-grained phase-coexistence simulations and microscopy experiments. Importantly, ΔK280 mutation promotes ß-sheet formation of six motifs (especially PHF6), increases the hydrophobic solvent exposure of PHF6* and PHF6, and enhances hydrophobic, hydrogen bonding, and cation-π interactions involving most of the motifs, thus facilitating the phase separation of K18. Notably, ΔK280 alters the interaction network among the six motifs, inducing the formation of K18 conformations with high ß-sheet contents and collapse degree. Coarse-grained simulations on full-length tau reveal that ΔK280 promotes tau LLPS by enhancing the hydrophobic interactions involving the microtubule-binding domain. These findings offer detailed mechanistic insights into ΔK280-induced tau pathogenesis, providing potential targets for therapeutic intervention.

Effect of clearance volume on the internal flow characteristics and output performance of oil-gas multiphase reciprocating pump.

In the production of oil and natural gas, excessive clearance volume is an important factor affecting the normal operation of oil-gas multiphase pump. Currently, little research has been conducted on the effect of clearance volume on the output characteristics of multiphase pump at home and abroad, leading to extremely low efficiency in the field application of multiphase pump. Therefore, this study conducted numerical calculations on the internal flow characteristics and output performance of multiphase pump under different clearance volumes using FLUENT software. Results show that pressure and fluid velocity gradually decrease as the clearance volume increases. Simultaneously, the number and intensity of vortex flow gradually increase, media pressurization speed becomes slower, and the lag angle of the discharge valve opening becomes larger. Moreover, under conditions with a higher gas volume fraction, multiphase pump with larger clearance volumes experiences gas locking. Furthermore, this study provides a theoretical basis for the reasonable design of clearance volume for multiphase pump by drawing a relationship curve between gas volume fraction and clearance volume. These research findings can provide theoretical support for the performance optimization and design improvement of multiphase pumps.

Regulating solvated sheath with anion chelant enables 4.6 V ultra-stable commercial LiCoO2.

Increasing cut-off voltage of lithium cobalt oxide (LCO) (> 4.6 V) is an effective strategy to satisfy the ever-increasing demand for high energy density. However, the irreversible phase transition significantly destroys the structure of high-voltage LCO, especially the surface lattice. Considering that the structural stability of LCO is primarily dominated by the intrinsic merits of electrode-electrolyte interface (EEI), we explored and disclosed the operating mechanism of anion chelating agent tris(pentafluorophenyl) borane (TPFPB) and regulate the CEI layer on LCO electrode. Benefiting from the high HOMO energy level and preferential decomposition of TPFPB-PF6-, a robust LiF-rich CEI layer is constructed and greatly improves the stability of electrode/electrolyte interface. The well-designed electrolyte composed of 1 mol L-1 LiPF6 in EC/EMC with TPFPB additives endows Li/LCO half cells and 4 Ah Gr/LCO pouch cell with enhanced cycling stability under a high voltage condition. This work provides pave a new direction for the development of economical high-voltage LIBs.

Magnetic-field-controlled positioning of magnetic domain wall in tie-shaped asymmetric nanowire and its application for magnetic field detection.

With topological spin texture, magnetic domain walls have soliton-like dynamic behaviors in magnetic nanowires, which can be used in information transmission and storage technology. Therefore, precisely controlling the dynamic behavior of the magnetic domain wall and its pinning behavior is one of the important technical challenges in realizing domain-wall-based spintronic devices. In this work, a geometrically defect-free scheme for domain wall pinning/depinning is proposed using micromagnetic simulations based on a tie-shaped asymmetric nanowire, which can precisely control the position of the magnetic domain wall in an external magnetic field. The results show that the domain wall in tie-shaped nanowires exhibits excellent linear response and ultrafast time response to external magnetic fields, which endow them with potential applications for high-frequency weak-magnetic-field detection. We further propose a scheme for constructing a magnetic-field sensor using the tie-structured nanowire, and we study its feasibility.

Improving treatment plan and mental health in children with abdominal infection for broad-spectrum bacterial infections.

BACKGROUND: Pediatric abdominal infection is a common but serious disease that requires timely and effective treatment. In surgical treatment, accurate diagnosis and rational application of antibiotics are the keys to improving treatment effects. AIM: To investigate the effect of broad-spectrum bacterial detection on postoperative antibiotic therapy. METHODS: A total of 100 children with abdominal infection who received surgical treatment in our hospital from September 2020 to July 2021 were grouped. The observation group collected blood samples upon admission and sent them for broad-spectrum bacterial infection nucleic acid testing, and collected pus or exudate during the operation for bacterial culture and drug sensitivity testing; the control group only sent bacterial culture and drug sensitivity testing during the operation. RESULTS: White blood cell count, C-reactive protein, procalcitonin, 3 days after surgery, showed better postoperative index than the control group (P < 0.05). The hospital stay in the observation group was significantly shorter than that in the control group. The hospitalization cost in the observation group was significantly lower than that in the control group, and the difference between the two groups was statistically significant (P < 0.05). CONCLUSION: Early detection of broad-spectrum bacterial infection nucleic acids in pediatric abdominal infections can help identify pathogens sooner and guide the appropriate use of antibiotics, improving treatment outcomes and reducing medical costs to some extent.

Carbon dots-loaded cellulose nanofibrils hydrogel incorporating Bi2O3/BiOCOOH for effective adsorption and photocatalytic degradation of lignin.

A novel photocatalytic adsorbent, a cellulose nanofibrils based hydrogel incorporating carbon dots and Bi2O3/BiOCOOH (designated as CCHBi), was developed to address lignin pollution. CCHBi exhibited an adsorption capacity of 435.0 mg/g, 8.9 times greater than that of commercial activated carbon. This enhanced adsorption performance was attributed to the 3D porous structure constructed using cellulose nanofibrils (CNs), which increased the specific surface area and provided additional sorption sites. Adsorption and photocatalytic experiments showed that CCHBi had a photocatalytic degradation rate constant of 0.0140 min-1, 3.1 times higher than that of Bi2O3/BiOCOOH. The superior photocatalytic performance of CCHBi was due to the Z-scheme photocatalytic system constructed by carbon dots-loaded cellulose nanofibrils and Bi2O3/BiOCOOH, which facilitated the separation of photoinduced charge carriers. Additionally, the stability of CCHBi was confirmed through consecutive cycles of adsorption and photocatalysis, maintaining a removal efficiency of 85 % after ten cycles. The enhanced stability was due to the 3D porous structure constructed by CNs, which safeguarded the Bi2O3/BiOCOOH. This study validates the potential of CCHBi for high-performance lignin removal and promotes the application of CNs in developing new photocatalytic adsorbents.

Single- versus multi-visit approach for fragment reattachment in complicated crown-root fractures: a cohort study.

BACKGROUND: Complicated crown-root fractures are a type of tooth fracture that involves the enamel, dentin, and cementum and accompanied by pulp exposure. The treatment of a complicated crown-root fracture is always challenging due to the difficulties in achieving a hermetic seal and a stable restoration with a fracture level close to the crestale bone level. This study aimed to evaluate and compare the efficacy of single-visit and multi-visit approaches for fragment reattachment in complicated crown-root fractures of anterior teeth. METHODS: Two cohort consist of 10 adolescent patients in each group at both genders, who suffered from permanent anterior tooth complicated crown-root fracture were included. Fragment reattachment with root canal treatment was performed with either single or multiple-visit approach. Single visit fragment attachement combined with root cannel therapy was conducted in single-visit approach group immediately after injury. Fragment attachment, root cananel therapy and post resoration were performed during three times ' clinical visit in multi-visit approach group. RESULTS: All the patients in both groups achieved satisfactory aesthetic results one year after fragment reattachment. Patients who underwent a multi-visit approach had a significantly shorter operative duration, less intra-operative pain and fatigue, slightly better periodontal health at an early stage, and a decreased incidence of temporomandibular joint disorders compared to those who underwent a single-visit approach. However, multiple visits approach may increase the risk of fragment detachment postoperatively. CONCLUSION: Fragment reattachment a reliable but temporary technique for adolescent patients who have suffered from complicated crown-root fractures. Multi-visit approach showed similar effecacy to single-visit approach but with slightly less complications. The choose of these two merhos should depend on the specific patient situation and patient compliance. TRIAL REGISTRATION: This prospective cohort study was retrospectively registered in Chinese Clinical Trial Registry (ChiCTR2300076811) on 19/10/2023.

The first description of mucous membrane pemphigoid induced by enalapril maleate: a case report.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease (AIBD). Some reports suggest that it has a drug-related pathogenesis especially anti-hypertensive drug. CASE PRESENTATION: A 67-year-old man with a 7-year history of essential hypertension was prescribed enalapril maleate for 5 months. He presented at our department with pain, ulcers, and blisters on the oral mucosa. We performed clinical, histopathology, and direct immunofluorescence examinations, and findings were consistent with the diagnostic criteria for MMP. Consequently, we consulted with the cardiovascular physician and agreed to discontinue the enalapril maleate replacing it with irbesartan/hydrochlorothiazide tablets and topical corticosteroid therapies instead. The lesions healed without recurrence. CONCLUSIONS: ABID induced by antihypertensive drugs have been reported, and enalapril maleate has been implicated as an antihypertensive agent that may trigger AIBDs, such as MMP. This case highlights the potential relationship between antihypertensive drugs and MMP, of which clinicians should be aware to accurately diagnose and promptly relieve patients' pain.

Effects of Ferroelastic Domain Walls on the Macroscopic Transport and Photoluminescent Properties of Bulk CsPbBr3 Single Crystals.

The all-inorganic halide perovskite CsPbBr3 has emerged as an excellent class of semiconductive and optoelectronic materials, in which its excellent properties are strongly related to the dynamics of its microstructures, i.e., ferroelastic domain walls. Here, the influence of ferroelastic domain walls on the macroscopic charge transport and photoluminescent properties in bulk single-crystal CsPbBr3 is experimentally and intrinsically studied across wide temperature intervals. The larger area of the same domain orientation, along with denser and thinner domain walls in a bulk CsPbBr3 single crystal, is formed through the Pnma↔P4/mbm↔Pm3̅m phase transitions. Remarkable motion of the domain walls near the P4/mbm↔Pm3̅m transition point is observed using in situ polarized optical microscopy. We initially observed a sharp decrease in resistivity after inducing larger areas with long-range order and denser, thinner domain walls in the temperature range from 273 to 343 K upon heating. In addition, the ferroelastic domain walls modulate exciton-phonon interactions and enhance radiative recombination in the CsPbBr3 single crystal, which correlates with the decrease in resistivity. These results will motivate strategies to design high-performance semiconductive and optoelectronic materials or devices by inducing specific ferroelastic domain walls in metal halide perovskites.

Mild condition lignin modification enabled high-performance anticorrosive polyurethane coating.

The diverse active hydroxyl groups of lignin pose challenges in the preparation of lignin-based polyurethane coatings with exceptional long-term anticorrosive properties. Here, the dense and defect-free lignin-based polyurethane coating with a thickness of 25 ± 5 µm was successfully synthesized using a mild hydroxypropyl lignin modification approach, exhibiting outstanding barrier properties (|Z| > 109 Ω cm2) and long-term anti-corrosion performance exceeding 120 d. Under ambient conditions (i.e., 25 °C and atmospheric pressure), propylene oxide was directly blended with the alkali solution of lignin to effectively convert phenolic hydroxyl groups into more reactive aliphatic hydroxyl groups, while also minimizing the significant increase in molecular weight caused by lignin condensation. As a result, the high crosslinking density of lignin polyurethane coatings effectively prevented the penetration of corrosive media and enhanced the long-term corrosion resistance of the coatings. Overall, the results demonstrate that a mild hydroxypropyl modification process is an effective and facile strategy to prepare highly reactive lignin-based polyols, which is crucial for the development of high-performance bio-based polyurethane anticorrosive coatings.

Simultaneous thoracoscopic surgery in patients with atrial fibrillation and early-stage lung cancer.

OBJECTIVES: Atrial fibrillation (AF) and early-stage lung cancer can both be treated under thoracoscopy. This study aims to evaluate the feasibility and safety of simultaneous thoracoscopic surgery for atrial fibrillation and early-stage lung cancer. METHODS: This was a single-center, retrospective study of 865 patients with paroxysmal or non-paroxysmal AF who underwent surgical ablation between October 2014 and December 2021. Patients were divided into two groups according to whether they have undergone simultaneous thoracoscopic early-stage lung cancer surgery and resulting in 24 pairs of patients. RESULTS: In total, 48 patients (24 matched pairs) were analyzed. The age was 63.71 ± 8.43 years. Procedure time and postoperative mechanical ventilation time were significantly lower in the group AF than group AFLC (Atrial fibrillation and lung cancer) (140.38 ± 27.53 vs. 230.79 ± 59.06 min, P<0.001; 5 vs 6.5 h, P = 0.002). There was no significant difference between the groups in terms of operative bleeding volume (90.00 ± 29.78 vs 85.83 ± 53.56 ml, P = 0.741), total postoperative drainage volume (1020.83 ± 516.5 vs 1406.25 ± 840.33 ml, P = 0.067), ICU (intensive care unit) length of stay (LOS) (43.5 vs 44 h, P = 0.33), hospitalization LOS (9.29 ± 1.92 vs 8.58 ± 1.98 days, P = 0.214) and incidence of freedom from AF or complications. CONCLUSIONS: Simultaneous thoracoscopic surgical AF ablation and early-stage lung cancer is safe and feasible. It can be used as an alternative method for coexisting atrial fibrillation and lung cancer with acceptable operative risks.

Current mRNA-based vaccine strategies for glioma treatment.

Gliomas are one of the most aggressive types of brain tumors and are associated with high morbidity and mortality rates. Currently, conventional treatments for gliomas such as surgical resection, radiotherapy, and chemotherapy have limited effectiveness, and new approaches are needed to improve patient outcomes. mRNA-based vaccines represent a promising therapeutic strategy for cancer treatment, including gliomas. Recent advances in immunotherapy using mRNA-based dendritic cell vaccines have shown great potential in preclinical and clinical trials. Dendritic cells are professional antigen-presenting cells that play a crucial role in initiating and regulating immune responses. In this review, we summarize the current progress of mRNA-based vaccines for gliomas, with a focus on recent advances in dendritic cell-based mRNA vaccines. We also discuss the feasibility and safety of mRNA-based clinical applications for gliomas.

Circ_0006174 Upregulates IGF1R to Enhance Radioresistance and Tumorigenesis in Colorectal Cancer via miR-940 Suppression.

Colorectal cancer (CRC) is one of the most common malignancies all over the world. Increasing evidence has revealed that circular RNAs (circRNAs) are involved in the progression of CRC. In this study, we aimed to investigate the role and underlying mechanism of circ_0006174 in the development and radiosensitivity of CRC. Circ_0006174, microRNA-940 (miR-940), and insulin-like growth factor 1 receptor (IGF1R) expression levels were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). The radiosensitivity of cells also was assessed using colony formation assay. Besides, cell proliferation, apoptosis, migration, and invasion were detected by cell counting kit-8 (CCK-8), flow cytometry, and transwell assays. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the relationship between miR-940 and circ_0006174 or IGF1R. IGF1R protein level was examined using western blot. A xenograft tumor model was used to verify the function of circ_0006174 in CRC tumor growth in vivo. Circ_0006174 and IGF1R levels were elevated and miR-940 expression was decreased in CRC tissues and cells. Circ_0006174 knockdown enhanced the radiosensitivity of CRC cells by regulating cell proliferation, apoptosis, migration, and invasion in vitro. In mechanism, circ_0006174 served as a sponge for miR-940 to upregulate IGF1R expression. Moreover, circ_0006174 silencing suppressed CRC growth in vivo. Circ_0006174 boosts radioresistance of CRC cells at least partly through upregulating IGF1R expression by sponging miR-940, providing a novel theoretical basis for CRC therapy.