RCHY1 and OPTN are required for melanophagy, selective autophagy of melanosomes.

Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, ß-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited ß-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. ß-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy.

Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.

BACKGROUND: The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. OBJECTIVES: This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. METHODS: RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. RESULTS: This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. CONCLUSIONS: This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss.

Low- or standard-dose edoxaban versus antiplatelet therapy for leaflet thrombus and cerebral thromboembolism after TAVR: A prespecified analysis of randomized ADAPT-TAVR trial.

BACKGROUND: The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. METHODS: In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. RESULTS: Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P = .03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P = .58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. CONCLUSIONS: In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction.

Surgical Outcomes in Non-Small Cell Lung Cancer with Distant Metastasis: The Prognostic Significance of Delayed Metastasis Diagnosis.

BACKGROUND: The diagnosis of distant metastasis on preoperative examinations for non-small cell lung cancer (NSCLC) can be challenging, leading to surgery for some patients with uncertain metastasis. This study evaluated the prognostic impact of delayed diagnosis of metastasis on patients who underwent upfront surgery. METHODS: The study enrolled patients who underwent lobectomy or pneumonectomy for NSCLC between June 2010 and December 2017 and evaluated the presence of distant metastasis before surgery. Overall survival (OS) for patients with stage IV cancer was compared with that for patients without metastasis, and the prognostic factors were analyzed. RESULTS: Of 3046 patients (mean age, 63 years; 1770 men), 100 (3.3 %) had distant metastasis, diagnosed preoperatively in 1.4 % (42/3046) and postoperatively in 1.9 % (58/3046) of the patients. The two most common metastasis sites diagnosed after surgery were contralateral lung (22/58, 37.9 %) and ipsilateral pleura (16/58, 27.6 %). The OS (median, 42.7 months) for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer (P = 0.865), whereas the OS (median OS, 91.7 months) for the patients with stage IV cancer diagnosed preoperatively was better than for the patients with stage IIIB cancer (P = 0.001). Among the patients with distant metastasis, squamous cell type (hazard ratio [HR], 3.15; P = 0.002) and systemic treatment for metastasis (HR, 2.42; P = 0.002) were independent predictors of worse OS. CONCLUSIONS: Among NSCLC patients undergoing upfront surgery, the OS for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer. For patients with stage IV disease, squamous cell type and systemic treatment for metastasis were prognostic factors for poorer OS.

Assessing the protection elicited by virus-like particles expressing the RSV pre-fusion F and tandem repeated G proteins against RSV rA2 line19F infection in mice.

Excessive pulmonary inflammation is the hallmark of respiratory syncytial virus (RSV) infection hindering efficacious RSV vaccine development. Yet, the vast majority of the experimental RSV vaccine studies use laboratory-adapted RSV strains that do not reflect the highly pathogenic and inflammatory nature of the virus found in clinical settings. Here, we re-evaluated the protective efficacy of the virus-like particle (VLP) vaccine co-expressing the pre-fusion (pre-F) protein and G protein with tandem repeats (Gt) reported in our previous study against the recombinant RSV rA2-line19F strain, which inflicts severe mucus production and inflammation in mice. VLP vaccine immunization elicited virus-specific serum antibody responses that mediated RSV rA2-line19F virus neutralization. VLP vaccine immunization promoted Th1 immune response development in the spleens and CD8 + T cell influx into the lungs of mice, which are essential for efficient viral clearance and dampened inflammatory response. When compared to the VLPs expressing only the pre-F antigen, those co-expressing both pre-F and Gt antigens conferred better protection in mice against rA2-line19F challenge infection. Overall, our data suggest that the pre-clinical VLP vaccine co-expressing RSV pre-F and Gt antigens can effectively protect mice against RSV strains that resemble pathogenic clinical isolates.

NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues.

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Ancistrocladus tectorius Extract Inhibits Obesity by Promoting Thermogenesis and Mitochondrial Dynamics in High-Fat Diet-Fed Mice.

Root extracts of Ancistrocladus tectorius (AT), a shrub native to China, have been shown to have antiviral and antitumor activities, but the anti-obesity effects of AT aerial parts, mainly the leaves and stems, have not been investigated. This study is the first to investigate the anti-obesity effects and molecular mechanism of AT 70% ethanol extract in 3T3-L1 adipocytes and high-fat diet (HFD)-fed C57BL/6J mice. Treatment with AT extract inhibited lipid accumulation in 3T3-L1 cells and decreased the expression of adipogenesis-related genes. AT extract also upregulated the mRNA expression of genes related to mitochondrial dynamics in 3T3-L1 adipocytes. AT administration for 12 weeks reduced body weight and organ weights, including liver, pancreas, and white and brown adipose tissue, and improved plasma profiles such as glucose, insulin, homeostasis model assessment of insulin resistance, triglyceride (TG), and total cholesterol in HFD-fed mice. AT extract reduced HFD-induced hepatic steatosis with levels of liver TG and lipogenesis-related genes. AT extract upregulated thermogenesis-related genes such as Cidea, Pgc1α, Ucp1, Prdm16, Adrb1, and Adrb3 and mitochondrial dynamics-related genes such as Mff, Opa1, and Mfn2 in brown adipose tissue (BAT). Therefore, AT extract effectively reduced obesity by promoting thermogenesis and the mitochondrial dynamics of BAT in HFD-fed mice.

Whey Peptide Alleviates Muscle Atrophy by Strongly Regulating Myocyte Differentiation in Mice.

Background and Objectives: Muscle atrophy occurs when protein degradation exceeds protein synthesis, resulting in imbalanced protein homeostasis, compromised muscle contraction, and a reduction in muscle mass. The incidence of muscle atrophy is increasingly recognized as a significant worldwide public health problem. The aim of the current study was to evaluate the effect of whey peptide (WP) on muscle atrophy induced by dexamethasone (DEX) in mice. Materials and Methods: C57BL/6 mice were divided into six groups, each consisting of nine individuals. WPs were orally administered to C57BL/6 mice for 6 weeks. DEX was administered for 5-6 weeks to induce muscle atrophy (intraperitoneal injection, i.p.). Results: Microcomputer tomography (CT) analysis confirmed that WP significantly increased calf muscle volume and surface area in mice with DEX-induced muscle atrophy, as evidenced by tissue staining. Furthermore, it increased the area of muscle fibers and facilitated greater collagen deposition. Moreover, WP significantly decreased the levels of serum biomarkers associated with muscle damage, kidney function, and inflammatory cytokines. WP increased p-mTOR and p-p70S6K levels through the IGF-1/PI3K/Akt pathway, while concurrently decreasing protein catabolism via the FOXO pathway. Furthermore, the expression of proteins associated with myocyte differentiation increased noticeably. Conclusions: These results confirm that WP reduces muscle atrophy by regulating muscle protein homeostasis. Additionally, it is believed that it helps to relieve muscle atrophy by regulating the expression of myocyte differentiation factors. Therefore, we propose that WP plays a significant role in preventing and treating muscle wasting by functioning as a supplement to counteract muscle atrophy.

Recent Advances in Environmentally Friendly Dual-crosslinking Polymer Networks.

Environmentally friendly crosslinked polymer networks feature degradable covalent or non-covalent bonds, with many of them manifesting dynamic characteristics. These attributes enable convenient degradation, facile reprocessibility, and self-healing capabilities. However, the inherent instability of these crosslinking bonds often compromises the mechanical properties of polymer networks, limiting their practical applications. In this context, environmentally friendly dual-crosslinking polymer networks (denoted EF-DCPNs) have emerged as promising alternatives to address this challenge. These materials effectively balance the need for high mechanical properties with the ability to degrade, recycle, and/or self-heal. Despite their promising potential, investigations into EF-DCPNs remain in their nascent stages, and several gaps and limitations persist. This Review provides a comprehensive overview of the synthesis, properties, and applications of recent progress in EF-DCPNs. Firstly, synthetic routes to a rich variety of EF-DCPNs possessing two distinct types of dynamic bonds (i.e., imine, disulfide, ester, hydrogen bond, coordination bond, and other bonds) are introduced. Subsequently, complex structure- and dynamic nature-dependent mechanical, thermal, and electrical properties of EF-DCPNs are discussed, followed by their exemplary applications in electronics and biotechnology. Finally, future research directions in this rapidly evolving field are outlined.

PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine-Tryptophan Interactions in TM-4 Stability.

A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer's disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aß) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma-secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid-extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma-secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aß was reflected in the increased Aß oligomerization tendency and the accumulations of Aß in the brain from amyloid-PET, leading to EOAD.

Pyrogallol intermediates elicit beta-amyloid secretion via radical formation and alterations in intracellular trafficking, distinct from pyrogallol-generated superoxide.

This study unveils a novel role of pyrogallol (PG), a recognized superoxide generator, in inducing beta-amyloid (Aß) secretion in an Alzheimer's disease (AD) cellular model. Contrary to expectations, the analysis of dihydroethidium fluorescence and UV-VIS spectrum scanning reveals that Aß secretion arises from PG reaction intermediates rather than superoxide or other by-products. Investigation into Aß secretion mechanisms identifies dynasore-dependent endocytosis and BFA-dependent exocytosis as independent pathways, regulated by tiron, tempol, and superoxide dismutase. Cell-type specificity is observed, with 293sw cells showing both pathways, while H4sw cells and primary astrocytes from an AD animal model exclusively exhibit the Aß exocytosis pathway. This exploration contributes to understanding PG's chemical reactions and provides insights into the interplay between environmental factors, free radicals, and AD, linking occupational PG exposure to AD risk as reported in the literature.

Regulation of Corneal Stromal Cell Behavior by Modulating Curvature Using a Hydraulically Controlled Organ Chip Array.

Curvature is a critical factor in cornea mechanobiology, but its impact on phenotypic alterations and extracellular matrix remodeling of cornea stroma remains unclear. In this work, we investigated how curvature influences the corneal stroma using a hydraulically controlled curvature array chip. The responses of stromal cells to low, medium, and high curvatures were observed by preparing three phenotypes of corneal stromal cells: corneal keratocytes, fibroblasts, and myofibroblasts. Keratocytes exhibited phenotypic alterations in response to curvature changes, notably including a decrease in ALDH3 expression and an increase in α-SMA expression. For focal adhesion, corneal fibroblast and myofibroblasts showed enhanced vinculin localization in response to curvature, while corneal keratocytes presented reduced vinculin expression. For cell alignment and ECM expression, most stromal cells under all curvatures showed a radially organized f-actin and collagen fibrils. Interestingly, for corneal fibroblast under medium curvature, we observed orthogonal cell alignment, which is linked to the unique hoop and meridional stress profiles of the curved surface. Furthermore, lumican expression was upregulated in corneal keratocytes, and keratocan expression was increased in corneal fibroblasts and myofibroblasts due to curvature. These results demonstrate that curvature influences both the phenotype of corneal stromal cells and the structural organization of corneal stroma tissue without any external stimuli. This curvature-dependent behavior of corneal stromal cells presents potential opportunities for creating therapeutic strategies for corneal shape dysfunctions.

Hidden underlying mechanisms for changes in mesozooplankton communities: Transport and eddy driven changes.

Mesozooplankton communities have been used extensively as reliable climate change indicators, mainly because of their rapid growth and sensitivity to environmental changes. This study explored the modifications in the taxonomic composition of the mesozooplankton community and the associated physical changes of transport-driven, eddy-driven, and marine heatwaves in the summers of the last 14 years (2009-2022) within the mixed layer of the Ulleung Basin in the East Sea/Japan Sea, where surface waters have rapidly warmed in recent decades. A slight increase was observed in the abundance of mesozooplankton from 2009 (3709 inds.m-3) to 2022 (4231 inds.m-3), with two notable peaks in 2015 (11,377 inds.m-3) and 2020 (11,184 inds.m-3), which was mainly attributed to the prevalence of Noctiluca scintillans. The first peak in 2015 showed thaliaceans to be the next dominant taxa, in which the southward direction of meandering in East Korea Warm Current (EKWC), presence of the Ulleung warm eddy, lower volume of the Western Channel (V-west) of the Korea Strait, and marine heatwaves (MHWs) did not occur. In contrast to the first peak, the second peak in 2020 showed Pyrocystis pseudonoctiluca to be the next dominant species, which may have been transported and advected by the strong V-west and eastward direction of the EKWC and the occurrence of MHWs that allowed the persistence of the subtropical species P. pseudonoctiluca. Overall, the significant increases in the second dominant mesozooplankton taxa appeared to be affected by physical changes, including transport or eddy-driven changes, along with the occurrence of strong V-west, the direction of the EKWC, and the occurrence of MHWs, which may synergistically influence the increase in the second dominant taxa during summer. This study highlights the complex interplay between notable variations in mesozooplankton communities and environmental factors, highlighting the potential consequences of different physical changes (transport-driven and eddy-driven) in this regional ocean.

Comparison of the impact of longitudinal body mass index changes on cardiac arrest risk between normal and overweight populations.

BACKGROUND: Being overweight is a key modifiable risk factor for cardiovascular disease. However, the impact of longitudinal changes in body mass index (BMI) on the risk of out-of-hospital cardiac arrests (OHCA) remains unclear, especially among overweight populations. METHODS: This nested case-control study utilized data from the Korean National Health Information Database between 2009 and 2018. A total of 23 453 OHCA patients, who underwent national health check-ups within 1 and 2-4 years before OHCA occurrence, and 31 686 controls, who underwent similar national health check-ups, were included. The study population was matched for sex, age and survival status. Conditional logistic regression was employed to analyse the odds ratios (ORs) and 95% confidence intervals (CIs) of each BMI per cent change in assessing the risk of OHCA occurrence within 1 year. RESULTS: A reverse J-shaped association between BMI per cent change and OHCA risk was observed, even among overweight populations. Among the overweight populations, weight loss significantly increased OHCA risk, with ORs (95% CI) of 4.10 (3.23-5.20) for severe weight loss (BMI decrease > 15%), 2.72 (2.33-3.17) for moderate weight loss (BMI decrease 10-15%) and 1.46 (1.35-1.59) for mild weight loss (BMI decrease 5-10%). Conversely, mild weight gain (BMI increase 5-10%) did not significantly increase OHCA risk. The impact of weight changes on the occurrence of OHCA differed by sex, being more prominent in males. CONCLUSIONS: Significant weight changes within a 4-year period increase the risk of OHCA with a reverse J-shaped association, even among overweight and obese individuals. Maintaining a stable weight could be a reliable public health strategy irrespective of the weight status, particularly for males.

Fatigue-Resistant Polymer Electrolyte Membranes for Fuel Cells.

In a hydrogen fuel cell, an electrolyte membrane conducts protons, but blocks electrons, hydrogen molecules, and oxygen molecules. The fuel cell often runs unsteadily, resulting in fluctuating water production, causing the membrane to swell and contract. The cyclic deformation can cause fatigue crack growth. This paper describes an approach to develop a fatigue-resistant polymer electrolyte membrane. The membrane is prepared by forming an interpenetrating network of a plastic electrolyte and a rubber. The former conducts protons, and the latter enhances fatigue resistance. The introduction of the rubber modestly reduces electrochemical performance, but significantly increases fatigue threshold and lifespan. Compared to pristine plastic electrolyte, Nafion, an interpenetrating network of Nafion and perfluoropolyether (PFPE) reduces the maximum power density by 20%, but increases the fatigue threshold by 175%. Under the wet/dry accelerated stress test, the fuel cell with the Nafion-PFPE membrane has a lifespan 1.7 times that of a fuel cell with the Nafion membrane.

Frequency-Dependent Dielectric Permittivity and Water Permeability in Ordered Mesoporous Silica-Grafted Fluorinated Polyimides.

Polymers with a low dielectric constant (Dk) are promising materials for high-speed communication networks, which demand exceptional thermal stability, ultralow Dk and dissipation factor, and minimum moisture absorption. In this paper, we prepared a series of novel low-Dk polyimide films containing an MCM-41-type amino-functionalized mesoporous silica (AMS) via in situ polymerization and subsequent thermal imidization and investigated their morphologies, thermal properties, frequency-dependent dielectric behaviors, and water permeabilities. Incorporating 6 wt.% AMS reduced the Dk at 1 MHz from 2.91 of the pristine fluorinated polyimide (FPI) to 2.67 of the AMS-grafted FPI (FPI-g-AMS), attributed to the free volume and low polarizability of fluorine moieties in the backbone and the incorporation of air voids within the mesoporous AMS particles. The FPI-g-AMS films presented a stable dissipation factor across a wide frequency range. Introducing a silane coupling agent increased the hydrophobicity of AMS surfaces, which inhibited the approaching of the water molecules, avoiding the hydrolysis of Si-O-Si bonds of the AMS pore walls. The increased tortuosity caused by the AMS particles also reduced water permeability. All the FPI-g-AMS films displayed excellent thermooxidative/thermomechanical stability, including a high 5% weight loss temperature (>531 °C), char residue at 800 °C (>51%), and glass transition temperature (>300 °C).

Comparison of Nefopam-Based Patient-Controlled Analgesia with Opioid-Based Patient-Controlled Analgesia for Postoperative Pain Management in Immediate Breast Reconstruction Surgery: A Randomized Controlled Trial.

Background/Objectives: Immediate breast reconstruction surgery (BRS) often leads to significant postoperative pain, necessitating effective analgesia. This study aimed to compare the analgesic efficacy of patient-controlled analgesia (PCA) containing nefopam with that of PCA containing opioids alone in patients undergoing BRS. Methods: A prospective, double-blind, randomized controlled trial was conducted on 120 patients undergoing immediate BRS after mastectomy. Patients were randomly allocated to receive PCA with fentanyl alone (Group F: fentanyl 10 mcg/kg), fentanyl and nefopam (Group FN: fentanyl 5 mcg/kg + nefopam 1 mg/kg), or nefopam alone (Group N: nefopam 2 mg/kg). Pain intensity (expressed in VASr and VASm), opioid consumption, and opioid-related complications were assessed. Results: PCA with nefopam, either alone or in combination with opioids, demonstrated non-inferior analgesic efficacy compared to PCA with fentanyl alone. At 24 h postoperatively, the VASr scores were 2.9 ± 1.0 in Group F, 3.1 ± 1.2 in Group FN, and 2.8 ± 0.9 in Group N (p = 0.501). At the same timepoint, the VASm scores were 4.1 ± 1.2 in Group F, 4.5 ± 1.5 in Group FN, and 3.8 ± 1.4 in Group N (p = 0.129). Significant differences among the three groups were observed at all timepoints except for PACU in terms of the total opioid consumption (p < 0.0001). However, there were no significant differences in opioid-related complications among the three groups. Conclusions: PCA with nefopam, whether alone or in combination with opioids, offers non-inferior analgesic efficacy compared to PCA with fentanyl alone in patients undergoing immediate BRS.

Effect of Preoperative Clear Liquid Consumption on Postoperative Recovery in Pediatric Patients Undergoing Minimally Invasive Repair of Pectus Excavatum: A Prospective Randomized Controlled Study.

Background/Objectives: Preoperative fasting guidelines traditionally aim to reduce pulmonary aspiration risk. However, concerns over the adverse effects of prolonged fasting have led to exploring alternatives. This study aimed to investigate the impact of preoperative clear liquid intake on postoperative outcomes in children undergoing minimally invasive repair of pectus excavatum (MIRPE). Methods: A prospective randomized controlled study was conducted on children aged 3-6 years scheduled for elective MIRPE. Patients were randomized into either a routine overnight fasting group (NPO) or a clear liquid group. The incidence and severity of emergence delirium (ED) were assessed using Pediatric Anesthesia Emergence Delirium (PAED) and Watcha scales at recovery room. Postoperative pain scores and opioid requirements were evaluated at intervals of 1-6 h, 6-12 h, and 12-24 h after surgery. Results: Fasting time was 178.6 ± 149.5 min and 608.9 ± 148.4 min in the clear liquid group compared and NPO group, respectively. The incidence of ED, measured by PAED and Watcha scales, was lower in the clear liquid group (PAED score ≥ 12: 55.6% vs. 85.2%, p = 0.037; Watcha score ≥ 3: 51.9% vs. 85.2%, p = 0.019). The highest PAED score recorded in the recovery room was significantly lower in the clear liquid group (11.4 ± 2.8 vs. 14.6 ± 2.8, p < 0.001). Clear liquid group showed significantly lower pain scores at 1-6, 6-12, and 12-24 h postoperatively. Additionally, clear liquid group had lower opioid requirement at 1-6 and 6-12 h postoperatively. Conclusions: Preoperative clear liquid consumption was associated with a lower incidence of ED in pediatric patients undergoing MIRPE.

A Brg1-Rme1 circuit in Candida albicans hyphal gene regulation.

Major Candida albicans virulence traits include its ability to make hyphae, to produce a biofilm, and to damage host cells. These traits depend upon expression of hypha-associated genes. A gene expression comparison among clinical isolates suggested that transcription factor Rme1, established by previous studies to be a positive regulator of chlamydospore formation, may also be a negative regulator of hypha-associated genes. Engineered RME1 overexpression supported this hypothesis, but no relevant rme1Δ/Δ mutant phenotype was detected. We reasoned that Rme1 may function within a specific regulatory pathway. This idea was supported by our finding that an rme1Δ/Δ mutation relieves the need for biofilm regulator Brg1 in biofilm formation. The impact of the rme1Δ/Δ mutation is most prominent under static or "biofilm-like" growth conditions. RNA sequencing (RNA-seq) of cells grown under biofilm-like conditions indicates that Brg1 activates hypha-associated genes indirectly via repression of RME1: hypha-associated gene expression levels are substantially reduced in a brg1Δ/Δ mutant and partially restored in a brg1Δ/Δ rme1Δ/Δ double mutant. An rme1Δ/Δ mutation does not simply bypass Brg1, because iron homeostasis genes depend upon Brg1 regardless of Rme1. Rme1 thus connects Brg1 to the targets relevant to hypha and biofilm formation under biofilm growth conditions.IMPORTANCECandida albicans is a major fungal pathogen of humans, and its ability to grow as a surface-associated biofilm on implanted devices is a common cause of infection. Here, we describe a new regulator of biofilm formation, RME1, whose activity is most prominent under biofilm-like growth conditions.

Crossprotection induced by virus-like particles containing influenza dual-hemagglutinin and M2 ectodomain.

Aims: To develop an effective universal vaccine against antigenically different influenza viruses. Materials & methods: We generated influenza virus-like particles (VLPs) expressing the H1 and H3 antigens with or without M2e5x. VLP-induced immune responses and crossprotection against H1N1, H3N2 or H5N1 viruses were assessed to evaluate their protective efficacy. Results: H1H3M2e5x immunization elicited higher crossreactive IgG antibodies than H1H3 VLPs. Upon challenge, both VLPs enhanced lung IgG, IgA and germinal center B-cell responses compared with control. While these VLPs conferred protection, H1H3M2e5x showed greater lung viral load reduction than H1H3 VLPs with minimal body weight loss. Conclusion: Utilizing VLPs containing dual-hemagglutinin, along with M2e5x, can be a vaccination strategy for inducing crossprotection against influenza A viruses.