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Autoactivation of lineage-determining transcription factors mediates bistable expression, generating distinct cell phenotypes essential for complex body plans. Classical type 1 dendritic cell (cDC1) and type 2 dendritic cell (cDC2) subsets provide nonredundant functions for defense against distinct immune challenges. Interferon regulatory factor 8 (IRF8), the cDC1 lineage-determining transcription factor, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32-kb enhancer, responsible for IRF8 autoactivation, is naturally suboptimized with low-affinity IRF8 binding sites. Introducing multiple high-affinity IRF8 sites into the Irf8 +32-kb enhancer causes a gain-of-function effect, leading to erroneous IRF8 autoactivation in specified cDC2 progenitors, redirecting them toward cDC1 and a novel hybrid DC subset with mixed-lineage phenotypes. Further, this also causes a loss-of-function effect, reducing Irf8 expression in cDC1s. These developmental alterations critically impair both cDC1-dependent and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of cDCs required for normal immune function., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background/aim: Epithelial ovarian cancer (EOC) is a lethal disease that is the fifth leading cause of cancer-related death in women. BAF312 (siponimod) is a potent and selective sphingosine-1-phosphate (S1P) receptor modulator that has been approved as a treatment for multiple sclerosis. In addition to its immunomodulatory action, BAF312 shows preclinical antitumor effects in several cancer types. This study sought to determine whether BAF312 had anticancer properties against EOC using in vitro and in vivo models., Materials and Methods: EOC cell lines A2780, SKOV3ip1, A2780-CP20, and SKOV3-TR were treated with BAF312 and tested for cell proliferation, apoptosis, and migration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting, and migration assays. We investigated the expression of sphingosine-1-phosphate receptor 1 (S1PR1) in most EOC cell lines through western blot analysis. To investigate potential mechanisms, western blot analysis was used to assess the expression of AKT serine/threonine kinase 1 (AKT) and extracellular-regulated kinase (ERK) after BAF312 treatment. We also created poly(D,L-lactide-co-glycolide) nanoparticles encapsulating BAF312 (PLGA-NP-BAF312) for in vivo therapy. The average size and zeta potential of PLGA-NP-BAF312 were determined using dynamic light scattering. The therapeutic efficacy of PLGA-NP-BAF312 was tested in an A2780 tumor-bearing orthotopic mouse model of EOC., Results: S1PR1 was overexpressed in most EOC cell lines. BAF312 significantly reduced cell proliferation and migration while inducing significant apoptosis in all EOC cell lines. PLGA-NP-BAF312 treatment significantly reduced tumor weights in A2780 tumor-bearing mice. Furthermore, the anticancer effects of BAF312 were associated with reduced phosphorylation of ERK and AKT., Conclusion: Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We report a new supramolecular porous crystal assembled from fused macrocycle-cage molecules. The molecule comprises a prismatic cage with three macrocycles radially attached. The molecules form a nanoporous crystal with one-dimensional (1D) nanochannels. The supramolecular porous crystal can take up lithium-ion electrolytes and achieve an ionic conductivity of up to 8.3 × 10 -4 S/cm. Structural analysis and density functional theory calculations reveal that efficient Li-ion electrolyte uptake, the presence of 1D nanochannels, and weak interactions between lithium ions and the crystal enable fast lithium-ion transport. Our findings demonstrate the potential of fused macrocycle-cage molecules as a new design motif for ion-conducting molecular crystals.

Artificial intelligence has been employed to simulate and optimize the performance of membrane capacitive deionization (MCDI), an emerging ion separation process. However, a real-time control for optimal MCDI operation has not been investigated yet. In this study, we aimed to develop a reinforcement learning (RL)-based control model and investigate the model to find an energy-efficient MCDI operation strategy. To fulfill the objectives, we established three long-short term memory models to predict applied voltage, outflow pH, and outflow electrical conductivity. Also, four RL agents were trained to minimize outflow concentration and energy consumption simultaneously. Consequently, actor-critic (A2C) and proximal policy optimization (PPO2) achieved the ion separation goal (<0.8 mS/cm) as they determined the electrical current and pump speed to be low. Particularly, A2C kept the parameters consistent in charging MCDI, which caused lower energy consumption (0.0128 kWh/m 3 ) than PPO2 (0.0363 kWh/m 3 ). To understand the decision-making process of A2C, the Shapley additive explanation based on the decision tree model estimated the influence of input parameters on the control parameters. The results of this study demonstrate the feasibility of RL-based controls in MCDI operations. Thus, we expect that the RL-based control model can improve further and enhance the efficiency of water treatment technologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Objective: While numerous in silico tools exist for target-based drug discovery, the inconsistent integration of in vitro data with predictive models hinders research and development productivity. This is particularly apparent during the Hit-to-Lead stage, where unreliable in-silico tools often lead to suboptimal lead selection. Herein, we address this challenge by presenting a CADD-guided pipeline that successfully integrates rational drug design with in-silico hits to identify a promising DDR1 lead., Methods: 2 × 1000 ns MD simulations along with their respective FEL and MMPBSA analyses were employed to guide the rational design and synthesis of 12 novel compounds which were evaluated for their DDR inhibition., Results: The molecular dynamics investigation of the initial hit led to the identification of key structural features within the DDR1 binding pocket. The identified key features were used to guide the rational design and synthesis of twelve novel derivatives. SAR analysis, biological evaluation, molecular dynamics, and free energy calculations were carried out for the synthesized derivatives to understand their mechanism of action. Compound 4c exhibited the strongest inhibition and selectivity for DDR1, with an IC 50 of 0.11 µM., Conclusions: The MD simulations led to the identification of a key hydrophobic groove in the DDR1 binding pocket. The integrated approach of SAR analysis with molecular dynamics led to the identification of compound 4c as a promising lead for further development of potent and selective DDR1 inhibitors. Moreover, this work establishes a protocol for translating in silico hits to real world bioactive druggable leads., Competing Interests: Declaration of competing interest The authors declare that there are no financial or interpersonal conflicts that could have influenced the research presented in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The objective is to comprehensively classify the types, topics and populations represented in the published lacrosse literature., Design: Mapping review. Protocol registration at Open Science Framework (https://osf.io/kz4e6)., Data Sources: 10 electronic databases were searched from inception to 31 March 2023., Eligibility Criteria: Peer-reviewed studies in English that included lacrosse were eligible. Publications without participant demographic or lacrosse-specific data were excluded., Results: We identified 498 articles pertaining to lacrosse, with 270 (54.2%) focused on player safety, 128 (25.7%) on sport science and 74 (14.9%) on clinical care. Musculoskeletal injury was the focus of 179 studies (35.9%), and the most common study design was cross-sectional (n=162, 32.5%). Most (n=423, 84.9%) originated in the USA. Over half (n=254, 51.0%) were published since 2017. 216 articles (43.4%) included female and male athletes, while 112 (22.5%) and 142 (28.5%) focused solely on female and male athletes, respectively. Collegiate athletes were the most frequent study population (n=277, 55.6%), and traditional field lacrosse was the focus of 298 (59.8%) articles. We observed that 77.1% (27/35) of quasiexperimental, 91.3% (21/23) of randomised controlled trials and 62.1% (18/29) of systematic reviews had a high or moderate risk of bias., Conclusion: The vast majority of lacrosse research originates from the USA, is in collegiate athletes, with a focus on player safety, and has a high risk of bias. With the sport's inclusion in the 2028 Olympics and growing global participation, higher quality research studies that are more inclusive and adaptable to diverse athletic groups and changing gameplay parameters are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Antimicrobial wound dressings offer enhanced efficacy compared to conventional dressing platforms by limiting bacterial infections, expediting the healing process, and creating a barrier against additional wound contamination. The use of silk derived from silkworm cocoons in wound healing applications is attributed to its exceptional characteristics. Compared to mulberry silk, sericin from non-mulberry cocoons has higher water exchange mobility and moisture retention. Eri, a non-mulberry silkworm, is an unexplored source of silk with an eco-friendly nature of production where the natural life cycle of silkworms is not disrupted, and no moths are sacrificed. This work reports on an eri silk cocoon-based scaffold decorated with silver nanoparticles as a wound dressing material effective against burn-wound-associated multiple-drug-resistant bacteria. The UV-vis spectroscopy showed maximum absorbance at 448 nm due to the surface plasmon resonance of silver nanoparticles. FT-IR spectra exhibited the functional groups in the eri silk proteins accountable for the reduction of Ag + to Ag 0 in the scaffold. SEM-EDX analysis revealed the presence of elemental silver, and XRD analysis confirmed their particle size of 5.66-8.82 nm. The wound dressing platform showed excellent thermal stability and hydrophobicity, fulfilling the criteria of a standard waterproof dressing material, and anticipating the prevention of bacterial biofilm formation in chronic wounds. The scaffold was found to be effective against both Staphylococcus aureus (MTCC 87) and Pseudomonas aeruginosa (MTCC 1688) multiple-drug-resistant pathogens. Electron microscopy revealed the bacterial cell damage, suggesting its bactericidal property. The results further revealed that the scaffold was both hemocompatible and cytocompatible, suggesting its potential application in chronic wounds such as burns. As an outcome, this study presents a straightforward, cost-effective, and sustainable way of developing a multifunctional wound dressing platform, suggesting its significant therapeutic potential in clinical and biomedical sectors and facile commercialization., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Purpose: Textbook outcome is a comprehensive measure used to assess surgical quality and is increasingly being recognized as a valuable evaluation tool. Delta-shaped anastomosis (DA), an intracorporeal gastroduodenostomy, is a viable option for minimally invasive distal gastrectomy in patients with gastric cancer. This study aims to evaluate the surgical outcomes and calculate the textbook outcome of DA., Materials and Methods: In this retrospective study, the records of 4,902 patients who underwent minimally invasive distal gastrectomy for DA between 2009 and 2020 were reviewed. The data were categorized into three phases to analyze the trends over time. Surgical outcomes, including the operation time, length of post-operative hospital stay, and complication rates, were assessed, and the textbook outcome was calculated., Results: Among 4,505 patients, the textbook outcome is achieved in 3,736 (82.9%). Post-operative complications affect the textbook outcome the most significantly (91.9%). The highest textbook outcome is achieved in phase 2 (85.0%), which surpasses the rates of in phase 1 (81.7%) and phase 3 (82.3%). The post-operative complication rate within 30 d after surgery is 8.7%, and the rate of major complications exceeding the Clavien-Dindo classification grade 3 is 2.4%., Conclusions: Based on the outcomes of a large dataset, DA can be considered safe and feasible for gastric cancer., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2024. Korean Gastric Cancer Association.)

Background: Methylcellulose has been applied as a primary binding agent to control the quality attributes of plant-based meat analogues. H owever, a great deal of effort has been made to search for hydrocolloids to replace methylcellulose because of increasing awareness of clean labels. In this study, a machine learning framework was proposed in order to describe and predict the flow behavior of six hydrocolloid solutions, and the predicted viscosities were correlated with the textural features of their corresponding plant-based meat analogues., Results: Different shear-thinning and Newtonian behaviors were observed depending on the type of hydrocolloid and the shear rate. Methylcellulose exhibited an increasing viscosity pattern with increasing temperature, compared to the other hydrocolloids. The machine learning algorithms (random forest and multilayer perceptron models) showed a better viscosity fitting performance than the constitutive equations (power law and Cross models). In addition, three hyperparameters of the multilayer perceptron model (optimizer, learning rate, and the number of hidden layers) were tuned using the Bayesian optimization algorithm., Conclusion: The optimized multilayer perceptron model exhibited superior performance in viscosity prediction (R 2  = 0.9944-0.9961/RMSE = 0.0545-0.0708). Furthermore, the machine learning-predicted viscosities overall showed similar patterns to the textural parameters of the meat analogues. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Nanostructured high-/medium-entropy compounds have emerged as important catalytic materials for energy conversion technologies, but complex thermodynamic relationships involved with the element mixing enthalpy have been a considerable roadblock to the formation of stable single-phase structures. Cation exchange reactions (CERs), in particular with copper sulfide templates, have been extensively investigated for the synthesis of multicomponent heteronanoparticles with unconventional structural features. Because copper cations within the host copper sulfide templates are stoichiometrically released with incoming foreign cations in CERs to maintain the overall charge balance, the complete absence of Cu cations in the nanocrystals after initial CERs would mean that further compositional variation would not be possible by subsequent CERs. Herin, we successfully retained a portion of Cu cations within the silver sulfide (Ag 2 S) and gold sulfide (Au 2 S) phases of Janus Cu 2-x S-M 2 S (M = Ag, Au) nanocrystals after the CERs, by partially suppressing the transformation of the anion sublattice that inevitably occurs during the introduction of external cations. Interestingly, the subsequent CERs on Janus Cu 1.81 S-M 2 S (M = Ag, Au), by utilizing the remnant Cu cations, allowed the construction of Janus Cu 1.81 S-Ag x Au y S, which preserved the initial heterointerface. The synthetic strategy described in this work to suppress the complete removal of the Cu cation from the template could fabricate the CER-driven heterostructures with greatly diversified compositions, which exhibit unusual optical and catalytic properties.

One-dimensional (1D) olivine iron phosphate (FePO 4 ) is widely proposed for electrochemical lithium (Li) extraction from dilute water sources, however, significant variations in Li selectivity were observed for particles with different physical attributes. Understanding how particle features influence Li and sodium (Na) co-intercalation is crucial for system design and enhancing Li selectivity. Here, we investigate a series of FePO 4 particles with various features and revealed the importance of harnessing kinetic and chemo-mechanical barrier difference between lithiation and sodiation to promote selectivity. The thermodynamic preference of FePO 4 provides baseline of selectivity while the particle features are critical to induce different kinetic pathways and barriers, resulting in different Li to Na selectivity from 6.2 × 10 2 to 2.3 × 10 4 . Importantly, we categorize the FePO 4 particles into two groups based on their distinctly paired phase evolutions upon lithiation and sodiation, and generate quantitative correlation maps among Li preference, morphological features, and electrochemical properties. By selecting FePO 4 particles with specific features, we demonstrate fast (636 mA/g) Li extraction from a high Li source (1: 100 Li to Na) with (96.6 ± 0.2)% purity, and high selectivity (2.3 × 10 4 ) from a low Li source (1: 1000 Li to Na) with (95.8 ± 0.3)% purity in a single step., (© 2024. The Author(s).)

Background: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury., Methods: This is a preclinical proof-of-concept study to determine the therapeutic effect of transcranial treatment with a low-power near-infrared laser in a mouse model of ischemic stroke. The laser treatment was performed before the middle cerebral artery occlusion with a filament. To determine the involvement of eNOS phosphorylation, unphosphorylatable eNOS S1176A knock-in mice were used. Each measurement was analyzed by a 2-way ANOVA to assess the effect of the treatment on cerebral blood flow with laser Doppler flowmetry, eNOS phosphorylation by immunoblot analysis, and stroke outcomes by infarct volumes and neurological deficits., Results: Pretreatment with a 1064-nm laser at an irradiance of 50 mW/cm 2 improved cerebral blood flow, eNOS phosphorylation, and stroke outcomes., Conclusions: Near-infrared II photobiomodulation could offer a noninvasive and low-risk adjunctive therapy for stroke injury. This new modality using a physical parameter merits further consideration to develop innovative therapies to prevent and treat a wide array of cardiovascular diseases., Competing Interests: Disclosures None.

This study was aimed to evaluate endogenous metabolic changes before and after cisplatin and radiation therapy in patients with cervical cancer via untargeted metabolomic analysis using plasma samples. A total of 13 cervical cancer patients were enrolled in this study. Plasma samples were collected from each patient on two occasions: approximately one week before therapy (P1) and after completion of cisplatin and radiation therapy (P2). Of the 13 patients, 12 patients received both cisplatin and radiation therapy, whereas one patient received radiation therapy alone. The samples were analyzed using the Ultimate 3000 coupled with Q Exactive TM Focus Hybrid Quadrupole-Orbitrap TM mass spectrometry (Thermo Fisher Scientific, Waltham, MA, USA). Chromatographic separation utilized a Kinetex C18 column 2.1×100 mm (2.6 μm) (Phenomenex, Torrance, CA, USA), and the temperature was maintained at 40°C. Following P2, there were statistically significant increases in the concentrations of indoxyl sulfate, phenylacetylglutamine, Lysophosphatidyethanolamine (LysoPE) (18:1), and indole-3-acetic acid compared with the concentrations observed at P1. Specifically, in the human papillomavirus (HPV) noninfection group, indoxyl sulfate, LysoPE (18:1), and phenylacetylglutamine showed statistically significant increases at P2 compared with P1. No significant changes in metabolite concentrations were observed in the HPV infection group. Indoxyl sulfate, LysoPE (18:1), phenylacetylglutamine, and indole-3-acetic acid were significantly increased following cisplatin and radiation therapy.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity ( p -value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Monocytes comprise two major subsets, Ly6C hi classical monocytes and Ly6C lo nonclassical monocytes. Notch2 signaling in Ly6C hi monocytes triggers transition to Ly6C lo monocytes, which require Nr4a1 , Bcl6 , Irf2 , and Cebpb . By comparison, less is known about transcriptional requirements for Ly6C hi monocytes. We find transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is highly expressed in Ly6C hi monocytes, but down-regulated in Ly6C lo monocytes. A few previous studies described the requirement of C/EBPα in the development of neutrophils and eosinophils. However, the role of C/EBPα for in vivo monocyte development has not been understood. We deleted the Cebpa +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBPα, reproducing the expected neutrophil defect. Surprisingly, we also found a severe and selective loss of Ly6C hi monocytes, while preserving Ly6C lo monocytes. We find that BM progenitors from Cebpa +37 -/- mice rapidly progress through the monocyte progenitor stage to develop directly into Ly6C lo monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBPα in maintaining Ly6C hi monocyte identity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: In traditional Asian medicine, dried rhizomes of Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma [CR]) have long been used to treat pain disorders that affect the head and face such as headaches. Furthermore, they have been used primarily for blood circulation improvement or as an analgesic and anti-inflammatory medicine. This study aimed to investigate the neuroprotective effects of a methanol extract of CR (CRex) on ischemic stroke in mice caused by middle cerebral artery occlusion (MCAO)., Methods: C57BL/6 mice were given a 1.5-h transient MCAO (MCAO control and CRex groups); CRex was administered in the mice of the CRex group at 1,000-3,000 mg/kg either once (single dose) or twice (twice dose) before MCAO. The mechanism behind the neuroprotective effects of CRex was examined using the following techniques: brain infarction volume, edema, neurological deficit, novel object recognition test (NORT), forepaw grip strength, and immuno-fluorescence staining., Results: Pretreating the mice with CRex once at 1,000 or 3,000 mg/kg and twice at 1,000 mg/kg 1 h before MCAO, brought about a significantly decrease in the infarction volumes. Furthermore, pretreating mice with CRex once at 3,000 mg/kg 1 h before MCAO significantly suppressed the reduction of forepaw grip strength of MCAO-induced mice. In the MCAO-induced group, preadministration of CRex inhibited the reduction in the discrimination ratio brought on by MCAO in a similar manner. CRex exhibited these effects by suppressing the activation of astrocytes and microglia, which regulated the inflammatory response., Conclusions: This study proposes a novel development for the treatment of ischemic stroke and provides evidence favoring the use of L. chuanxiong rhizomes against ischemic stroke., (© 2024. The Author(s).)

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis., (© 2024. The Author(s).)

In traditional Asian medicine, Ligusticum chuanxiong Hort also known as Conioselinum anthriscoides "Chuanxiong", is mainly used for improving blood circulation or for analgesic and anti-inflammatory purposes, but they also have a long history of use for pain disorders in the head and face, such as headache. Despite the possibility that the plant is effective for diseases such as cerebral infarction and vascular dementia (VaD), the mechanism of action is not well understood. To determine if the dried rhizomes of L. chuanxiong (Chuanxiong Rhizoma, CR) methanol extract (CRex) has activity in a VaD mice model. Through network analysis, we confirm that CR is effective in cerebrovascular diseases. In mice, we induce cognitive impairment, similar to VaD in humans, by chronically reducing the cerebral blood flow by performing bilateral common carotid artery stenosis (BCAS) and administering CRex for 6 weeks. We measure behavioral changes due to cognitive function impairment and use immunofluorescence staining to confirm if CRex can inhibit the activation of astrocytes and microglia involved in the inflammatory response in the brain. We quantify proteins involved in the mechanism, such as mitogen-activated protein kinases (MAPK), in the hippocampus and surrounding white matter, and analyze gene expression and protein interaction networks through RNA sequencing to interpret the results of the study. CRex administration rescued cognitive impairment relating to a novel object and inhibited the activation of astrocytes and microglia. Western blotting analysis revealed that CRex regulated the changes in protein expression involved in MAPK signaling such as extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38). The administration of CRex suppressed approximately 44% of the pathological changes in gene expression caused by BCAS. CRex extract effectively inhibited cognitive impairment caused by BCAS, and the mechanism through which this occurred is inhibited activation of astrocytes and microglia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lim, Lim and Cho.)

Levilactobacillus brevis KU15006, isolated from kimchi, exhibits pathogen-antagonistic and anti-diabetic activities; however, the safety of this strain has not been assessed. In the present study, L. brevis KU15006 was evaluated to elucidate its safety as a probiotic strain using phenotypic and genotypic analyses. Its safety was assessed using a minimum inhibitory concentration test comprising nine antibiotics, 26 antibiotic resistance genes, a single conjugative element, virulence gene analysis, hemolysis, cell cytotoxicity, mucin degradation, and toxic metabolite production. L. brevis KU15006 exhibited equal or lower minimum inhibitory concentration for the nine antibiotics than the cut-off value established by the European Food Safety Authority. It did not harbor antibiotic resistance and virulence genes. L. brevis KU15006 lacked β-hemolysis, mucin degradation, cytotoxicity against Caco-2 cells, gelatin liquefaction, bile salt deconjugation, and toxic metabolite production abilities. Based on the results, L. brevis KU15006, which has antagonistic and anti-diabetic effects, could be marketed as a probiotic in the future., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 10 11 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5-6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus , and higher levels of the metabolites that have immunogenic properties.

The regulation of proinflammatory mediators has been explored to promote natural healing without abnormal inflammation or autoimmune response induced by their overproduction. However, most efforts to control these mediators have relied on pharmacological substances that are directly engaged in biological cycles. It is believed that functional porous materials removing target mediators provide a new way to promote the healing process using their adsorption mechanisms. In this study, the Zr-based metal-organic frameworks (MOF)-808 (Zr 6 O 4 (OH) 4 (BTC) 2 (HCOO) 6 ) crystals are found to be effective at removing proinflammatory mediators, such as nitric oxide (NO), cytokines, and reactive oxygen species (ROS) in vitro and in vivo, because of their porous structure and surface affinity. The MOF-808 crystals are applied to an in vivo skin wound model as a hydrogel dispersion. Hydrogel containing 0.2 wt% MOF-808 crystals shows significant improvement in terms of wound healing efficacy and quality over the corresponding control. It is also proven that the mode of action is to remove the proinflammatory mediators in vivo. Moreover, the application of MOF-808-containing hydrogels promotes cell activation, proliferation and inhibits chronic inflammation, leading to increased wound healing quality. These findings suggest that Zr-based MOFs may be a promising drug-free solution for skin problems related to proinflammatory mediators., (© 2023 Wiley-VCH GmbH.)

The aberrant increase or dysregulation of cytosolic Zn 2+ concentration ([Zn 2+ ] cyt ) has been associated with cellular dysfunction and cytotoxicity. In this study, we postulated that Zn 2+ mediates the cytotoxicity of thiol-reactive electrophiles. This notion was grounded on earlier research, which revealed that thiol-reactive electrophiles may disrupt Zn 2+ -binding motifs, consequently causing Zn 2+ to be released from Zn 2+ -binding proteins, and leading to a surge in [Zn 2+ ] cyt . The thiol-reactive electrophiles N-ethylmaleimide (NEM) and diamide were observed to induce an increase in [Zn 2+ ] cyt , possibly through the impairment of Zn 2+ -binding motifs, and subsequent stimulation of reactive oxygen species (ROS) formation, resulting in cytotoxicity in primary cultured rat vascular smooth muscle cells. These processes were negated by the thiol donor N-acetyl-L-cysteine and the Zn 2+ chelator TPEN. Similar outcomes were detected with co-treatment involving Zn 2+ and Zn 2+ ionophores such as pyrithione or disulfiram. Moreover, TPEN was found to inhibit cytotoxicity triggered by short-term exposure to various thiol-reactive electrophiles including hydrogen peroxide, acrylamide, acrylonitrile, diethyl maleate, iodoacetic acid, and iodoacetamide. In conclusion, our findings suggest that cytosolic Zn 2+ acts as a universal mediator in the cytotoxic effects produced by thiol-reactive electrophiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Functionality in molecular electronics relies on inclusion of molecular orbital energy level within a transmission window. This can be achieved by designing the active molecule with accessible energy levels or by widening the window. While many studies have adopted the first approach, the latter is challenging because defects in the active molecular component cause low breakdown voltages. Here, it is shown that control over the packing structure of monolayer via supramolecular mixing transforms an inert molecule into a highly tunable rectifier. Binary mixed monolayer composed of alkanethiolates with and without carboxylic acid head group as a proof of concept is formed via a surface-exchange reaction. The monolayer withstands high voltages up to |4.5 V| and shows a dynamic rectification-external bias relationship in magnitude and polarity. Sub-highest occupied molecular orbital (HOMO) levels activated by the widened transmission window account for these observations. This work demonstrates that simple supramolecular mixing can imbue new electrical properties in electro-inactive organic molecules., (© 2023 Wiley-VCH GmbH.)

Vascular dementia (VD) is the second most prevalent dementia type, with no drugs approved for its treatment. Here, the effects of Banhabaekchulcheonma-Tang (BBCT) on ischemic brain injury and cognitive function impairment were investigated in a bilateral carotid artery stenosis (BCAS) mouse model. Mice were divided into sham-operated, BCAS control, L-BBCT (40 ml/kg), and H-BBCT (80 ml/kg) groups. BBCT's effects were characterized using the Y-maze test, novel object recognition test (NORT), immunofluorescence staining, RNA sequencing, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses. The NORT revealed cognitive function improvement in the H-BBCT group, while the Y-maze test revealed no significant difference among the four groups. The CD68+ microglia and GFAP+ astrocyte numbers were reduced in the H-BBCT group. Furthermore, H-BBCT treatment restored the dysregulation of gene expression caused by BCAS. The major BBCT targets were predicted to be cell division cycle protein 20 (CDC20), Epidermal growth factor (EGF), and tumor necrosis factor receptor-associated factor 1 (TRAF1). BBCT regulates the neuroactive ligand-receptor interaction and neuropeptide signaling pathways, as predicted by KEGG and GO analyses, respectively. BBCT significantly improved cognitive impairment in a BCAS mouse model by inhibiting microglial and astrocyte activation and regulating the expression of CDC20, EGF, TRAF1, and key proteins in the neuroactive ligand-receptor interaction and neuropeptide signaling pathways., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Targeted protein degradation (TPD) technology, such as proteolysis-targeting chimera (PROTAC), has become a new therapeutic modality. However, the degradation of undruggable proteins, such as those involved in protein-protein interactions (PPIs), using PROTAC is still limited owing to the difficulties in finding small-molecule binders of these proteins. To identify new chemical moieties that bind to the target sites of the protein of interest (POI), we conducted a site-specific and fragment-based covalent ligand screening using liquid chromatography-tandem mass spectrometry (LC-MS/MS). To apply the selected hits to the PROTAC approach, two-dimensional (2D) nuclear magnetic resonance (NMR) experiments were performed to evaluate the reversible binding of their analogs without covalent warheads. To proof the proposed approach, human mouse double minute (MDM)2 was selected as a model system since it is involved in PPIs and is known to be a degradable target protein. Western blot analysis showed that newly synthesized PROTACs, incorporated reversible analogs of screening hits, affected degradation in a dose- and time-dependent manner. This methodology makes it possible to use PROTAC technology to exploit previously undruggable proteins for TPD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Young Ho Jeon has patent #Pharmaceutical composition for preventing or treating hyper-proliferative disease including new small molecules inhibiting MDM2 protein pending to Korea University Sejong Campus. H.L., J.Y.L., H.J., H.Y.C., M.K., S.H.B., J.J., J.Y.K., and Y.H.J. have filled a provisional patent in the Korea related to this work., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Competing Interests: The authors have no potential conflicts of interest to disclose.

Background: Symptomatic benign prostatic hyperplasia (sBPH) is a potential risk factor for periprosthetic joint infection (PJI), a leading cause of implant failure and revision THA. However, the available evidence is mixed on whether this is the case., Questions/purposes: (1) What is the prevalence of sBPH in male recipients of primary THA by age group? (2) Do patients with sBPH compared with those without sBPH have higher 30-day, 90-day, and 2-year odds of PJI and higher 30-day and 90-day odds of urinary catheterization, urinary tract infection (UTI), and sepsis after primary THA? (3) Do patients with sBPH compared with those without sBPH have lower survivorship free from PJI-related revision at 5 years after THA?, Methods: The PearlDiver database was used as it provided the largest sample of patients across all payer types to perform longitudinal research. Between January 2010 and April 2021, 1,056,119 patients who underwent primary THA were identified. After applying the inclusion criteria (that is, male sex, minimum age of 18, and diagnosis of hip osteoarthritis) and exclusion criteria (that is, history of asymptomatic BPH or any other joint arthroplasty), 16% (172,866) of patients remained. A further 6% (59,500) of patients were excluded as they did not meet the minimum study follow-up of 2 years, leaving 11% (113,366) for analysis. Of those, patients with sBPH were matched to those without in a 1:4 ratio by age and comorbidities, including alcohol abuse, anemia, cardiovascular disorders, chronic pulmonary disease, diabetes mellitus, depression, obesity, peripheral vascular disorders, renal failure, and rheumatoid arthritis. Age and comorbidities of the two groups postmatch were balanced. Logistic regression was performed to analyze the odds for 30-day, 90-day, and 2-year postoperative complications. Survivorship free from PJI-related revision at 5 years after THA was estimated using the Kaplan-Meier method and compared with the log-rank test., Results: Among male recipients of primary THA ages 65 or older, 24% (11,319 of 47,426) had a medical history of sBPH. We found no difference in the odds of PJI at 30 days, 90 days, and 2 years after primary THA between the two groups. PJI occurred in 0.5% (62 of 11,819), 0.8% (97 of 11,819), and 1.3% (150 of 11,819) of patients with sBPH versus in 0.5% (227 of 47,103), 0.8% (360 of 47,103), and 1.2% (570 of 47,103) of those without sBPH within 30 days (OR 1.09 [95% CI 0.82 to 1.43]), 90 days (OR 1.07 [95% CI 0.85 to 1.34]), and 2 years (OR 1.05 [95% CI 0.87 to 1.25]) after THA, respectively. Patients with sBPH compared with those without had higher odds of 30-day and 90-day urinary catheterization (OR 5.00 [95% CI 3.64 to 6.88] and OR 5.36 [95% CI 4.04 to 7.13], respectively), 30-day and 90-day UTI (OR 2.18 [95% CI 1.88 to 2.54] and OR 2.55 [95% CI 2.26 to 2.87], respectively), and 30-day and 90-day sepsis (OR 1.55 [95% CI 1.11 to 2.13] and OR 1.43 [95% CI 1.10 to 1.83], respectively). We found no difference in survival free from PJI-related revision at 5 years after THA between patients with and without sBPH (98.3% [95% CI 98.1% to 98.6%] versus 98.1% [95% CI 98.1% to 98.2%]; p = 0.10)., Conclusion: sBPH is common among THA recipients, and surgeons should be aware of the added risk of postoperative urinary complications and sepsis in this subset that could lead to additional postoperative care requirements. Surgeons may consider perioperative measures such as preoperative use of short-form questionnaires to assess urinary symptoms, urology clearance or referral, and closer follow-up to improve care of sBPH patients undergoing THA. As currently available tools for assessing sBPH are limited and lack sensitivity as well as specificity, future studies may develop validated tools that can be used to quickly assess risk in sBPH patients before surgery., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 by the Association of Bone and Joint Surgeons.)

The aim of this study was to propose repeated and prolonged batch (RPB) assay as a promising specific anammox activity (SAA) methodology assessing the anammox activity under stressed salinity and pH conditions. Response surface analysis (RSA) was used as a regression tool to evaluate statistical significance. The feasibility of RPB was investigated at 0 to 15 g-NaCl/L of salinity and pH 6 to 8 with reflecting the results of preliminary SAA. As a result, conventional SAA was statistically insignificant. In addition, the RSA results obtained from repeated batch did not meet the statistical significance despite ten times iterative reaction. Interestingly, the RPB assay (i.e., applied both repeated and prolonged reaction) was effective to obtain the reliable results. Candidadus Brocadia and Candidadus Jettenia were functional anammox microbiome during RPB. Outcomes of this study suggest that RPB assay can be applied to accurately determine the anammox activity under various stressful conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Nurse turnover is often considered to be an outcome, and few studies have investigated its consequences in nursing care. The underlying mechanism of the nurse turnover-nurse outcome relationship has not been empirically investigated. Therefore, this study examines workgroup processes and nurse outcomes as the consequences of nurse turnover and the mediating effect of workgroup processes on the nurse turnover-nurse outcomes relationship., Methods: A cross-sectional design was adopted to investigate the data collected from 264 staff nurses. Furthermore, six-month turnover rates, workgroup processes (nurse-nurse collaboration, team cohesion), and nurse outcomes (job satisfaction, intent to leave) were utilized in the multivariate regression models., Results: Overall, 53 (24.4%) nurses had worked in nursing units with a zero six-month turnover rate. The average mean six-month turnover rate was 15.5%. Nurse turnover adversely affected nurses' job satisfaction and several subscales of team cohesion including task cohesion and social cohesion. Team cohesion partially mediated the relationship between nurse turnover and job satisfaction., Conclusion: Nurse turnover decreased job satisfaction and team cohesion, and team cohesion partially mediated the nurse turnover-nurse outcomes relationship. These findings provide evidence supporting the significant adverse effects of nurse turnover and suggest the potential role of workgroup processes in explaining the underlying mechanism of the relationship between nurse turnover and nurse outcomes., Implications for Nursing and Health Policy: Healthcare organizations must create a positive work environment to reduce nurse turnover. Further, states and countries should try to develop and establish nursing and health policies to prevent turnover., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bae, Kim and Myung.)

Background: Patients undergoing total hip arthroplasty (THA) commonly have osteoporosis for which bisphosphonates (BPs) are Food and Drug Administration (FDA)-approved for treatment. Bisphosphonate use post-THA is associated with decreased periprosthetic bone loss or revisions, and increased longevity of implants. However, evidence is lacking for preoperative bisphosphonate use in THA recipients. This study investigated the association between bisphosphonate use pre-THA and outcomes., Methods: A retrospective review of a national administrative claims database was conducted. Among THA recipients who had a prior diagnosis of hip osteoarthritis and osteoporosis/osteopenia, the treatment group (BP-exposed) consisted of patients who had a history of bisphosphonate use at least 1 year before THA; controls (BP-naive) comprised patients who did not have preoperative bisphosphonate use. The BP-exposed were matched to BP-naive in a 1:4 ratio by age, sex, and comorbidities. Logistic regressions were used to calculate the odds ratio for intraoperative and 1-year postoperative complications., Results: The BP-exposed group had significantly higher rates of intraoperative and 1-year postoperative periprosthetic fractures (odds ratio (OR): 1.39, 95% confidence interval (CI): 1.23, 1.57) and revisions (OR: 1.14, 95% CI: 1.04, 1.25) compared with the BP-naive controls. BP-exposed also experienced higher rates of aseptic loosening, dislocation, periprosthetic osteolysis, and stress fracture of the femur or hip/pelvis compared to the BP-naive controls, but these values were not statistically significant., Conclusion: The use of bisphosphonates in THA patients preoperatively is associated with higher rates of intraoperative and 1-year postoperative complications. These findings may impact the management of patients undergoing THA who have a prior diagnosis of osteoporosis/osteopenia and use of bisphosphonates., Level of Evidence: Retrospective Cohort Study (Level 3)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The objective of this study was to compare the maternal and neonatal outcomes following delayed cord clamping (DCC) versus immediate cord clamping (ICC) in twin pregnancies. This was a retrospective cohort study of 705 twin pregnancies who delivered at ≥ 24 weeks of gestation. Maternal and neonatal hemoglobin levels, blood transfusion, and neonatal outcomes were compared between DCC (n = 225) and ICC (n = 480) groups. Mean maternal predelivery and postpartum hemoglobin levels and the rate of postpartum hemoglobin drop ≥ 20% or maternal blood transfusion were comparable between the two groups. The DCC group had a significantly higher mean neonatal hemoglobin level (DCC vs. ICC: 17.4 ± 3.5 vs. 16.6 ± 2.7 g/dl, P = 0.010) but significantly lower rates of neonatal blood transfusion (DCC vs. ICC: 3.3% vs. 8.8%, P < 0.001) and respiratory distress syndrome (DCC vs. ICC: 6.7% vs. 15.2%, P < 0.001) than the ICC group. In conclusion, DCC compared with ICC in twin pregnancy was not associated with an increase of maternal postpartum bleeding complications, but it was associated with higher neonatal hemoglobin level and lower risks of neonatal blood transfusion and respiratory distress syndrome., (© 2023. Springer Nature Limited.)

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity., (© 2023 Kim et al.)

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising regenerative therapeutic approach for wound healing. To determine the effects of cultured MSCs as a 2D monolayer (2D-MSCs) and 3D spheroids (3D-MSCs) on their secretomes, and to examine the effect of 3D-MSC secretomes on endothelial cells (ECs) and MSCs in a burn injury mouse model. MSCs were cultured as 2D monolayers (2D-MSCs) and 3D spheroids (3D-MSCs) and their cellular characteristics were evaluated by western blotting. 2D-MSC and 3D-MSC secretomes (condition medium: CM) were analyzed using an angiogenic array. The activation of ECs by 2D-MSC and 3D-MSC CMs was examined in cellular proliferation, migration, and tube formation assays. The wound healing effects of 2D-MSCs and 3D-MSCs were determined in vivo using a burn injury mouse model. 3D culture conditions altered the markers of components that regulate cell survival, cytoskeletal, adhesion, and proliferation. Interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), IL-8, and chemokine (CXC motif) ligand 1 (CXCL1) were present at high levels in the CM of 3D-MSCs compared with 2D-MCs. 3D-MSC-CMs promoted the proliferation, migration, and tube formation of ECs. Furthermore, 3D-MSC treatment enhanced wound healing in a burn injury mouse model. 3D culture improves proangiogenic factors in the MSC secretome and 3D-MSCs represent a new cell-based treatment strategy for wound healing., Competing Interests: Declaration of competing interest All the authors report no relevant conflicts of interest for this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Deprescribing, the collaborative process between providers and patients to streamline medication regimen, may reduce the risk of adverse events following surgery among older adults with multimorbidity. However, barriers and facilitators to deprescribing for surgery has not been explored., Methods: We conducted a qualitative study of Primary Care Providers (PCP) and patients aged 65 and older who were scheduled for surgery. We used the Theoretical Domains Framework, which informed the interview guide and analysis., Results: A total of 16 participants (n=8 providers, n=8 patients) were included. Themes were regarding: 1) attitudes towards deprescribing before surgery, 2) perceived benefits of deprescribing before surgery, 3) patient-provider relationship and shared decision-making, 4) hope for surgery, 5) barriers to deprescribing before surgery, and 6) preferences for deprescribing follow-up., Conclusion: Our study findings regarding provider- and patient-related barriers and facilitators for deprescribing and desired processes before surgery may inform future deprescribing intervention targets before surgery., Competing Interests: Declaration of Competing Interest CMB is a co-author for UpToDate on multimorbidity and a reviewer for Dynamed for a chapter on falls. All other authors do not have any conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In vitro culture of bone marrow (BM) with Fms-like tyrosine kinase 3 ligand (Flt3L) is widely used to study development and function of type 1 conventional dendritic cells (cDC1). Hematopoietic stem cells (HSCs) and many progenitor populations that possess cDC1 potential in vivo do not express Flt3 and thus may not contribute to Flt3L-mediated cDC1 production in vitro. Here, we present a KitL/Flt3L protocol that recruits such HSCs and progenitors into the production of cDC1. Kit ligand (KitL) is used to expand HSCs and early progenitors lacking Flt3 expression into later stage where Flt3 is expressed. Following this initial KitL phase, a second Flt3L phase is used to support the final production of DCs. With this two-stage culture, we achieved approximately tenfold increased production of both cDC1 and cDC2 compared to Flt3L culture. cDC1 derived from this culture are similar to in vivo cDC1 in their dependence on IRF8, ability to produce IL-12, and induction of tumor regression in cDC1-deficient tumor-bearing mice. This KitL/Flt3L system for cDC1 production will be useful in further analysis of cDC1 that rely on in vitro generation from BM., (© 2023 Wiley-VCH GmbH.)

Lignin has potential as a substitute for natural antioxidants in cosmetics and food industries due to its radical scavenging ability and price competitiveness. The antioxidant activity of lignin depends on its structural properties, and they accordingly have synergy with natural antioxidants. Based on the structural characteristics, the antioxidant activity of ethanol organosolv lignin (EOL) and synergy with myricetin were investigated. The phenolic-OH content was a predominant factor in the antioxidant activity of EOL, and EOL-H with a higher phenolic-OH content and lower IC 50 value (0.17 mg/mL) covered a wide synergy range of 1:32-2:1 (EOL:myricetin). The synergistic effect was verified by comparing predicted and actual values based on ESR analysis, and the phenolic-OH ratio (>0.4) of myricetin and EOL for the synergy was suggested. In this respect, the results highlight the potential of lignin with high phenolic-OH content as a substitute for commercial antioxidants with superior activity and broad synergy ranges., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bacterial biofilms are communities of cells adhered to surfaces. These communities represent a predominant form of bacterial life on Earth. A defining feature of a biofilm is the three-dimensional extracellular polymer matrix that protects resident cells by acting as a mechanical barrier to the penetration of chemicals, such as antimicrobials. Beyond being recalcitrant to antibiotic treatment, biofilms are notoriously difficult to remove from surfaces. A promising, but relatively underexplored, approach to biofilm control is to disrupt the extracellular polymer matrix by enabling penetration of particles to increase the susceptibility of biofilms to antimicrobials. In this work, we investigate externally imposed chemical gradients as a mechanism to transport polystyrene particles into bacterial biofilms. We show that preconditioning the biofilm with a prewash step using deionized (DI) water is essential for altering the biofilm so it takes up the micro- and nanoparticles by the application of a further chemical gradient created by an electrolyte. Using different particles and chemicals, we document the transport behavior that leads to particle motion into the biofilm and its further reversal out of the biofilm. Our results demonstrate the importance of chemical gradients in disrupting the biofilm matrix and regulating particle transport in crowded macromolecular environments, and suggest potential applications of particle transport and delivery in other physiological systems.