Posttreatment experiences of reproductive concerns among young breast cancer survivors: A descriptive phenomenological study.

PURPOSE: The long-term fertility impact of cancer treatments is a significant concern for young breast cancer survivors. These reproductive concerns often become a persistent source of stress, negatively affecting their quality of life. This study aims to explore the reproductive concerns experienced by young breast cancer survivors post-treatment and the factors influencing their perceptions. METHODS: This phenomenological study utilized semi-structured interviews to collect data. Eighteen participants were recruited from a tertiary hospital in Mainland China. The interviews were transcribed verbatim and analysed using Colaizzi's method. RESULTS: Data analysis revealed five themes and fourteen subthemes: (1) multiple emotional burdens interwoven with concerns about fertility; (2) concerns about risks associated with reproduction; (3) dilemma of childrearing; (4) the significance of reproduction; (5) support needs from family, peers, and professionals. CONCLUSIONS: Young breast cancer survivors in China face significant challenges related to reproductive issues. Reproductive health is a crucial aspect of breast cancer survivorship care. Healthcare providers must be attentive to the reproductive concerns of survivors, recognize the importance of multidimensional support for positive adaptation, and offer tailored and ongoing interventions to manage reproductive health in young breast cancer survivors.

Hybrid Passive Cooling for Power Equipment Enabled by Metal-Organic Framework.

While providing electrical energy for human society, power equipment also consumes electricity and generate heat. Cooling equipment consumes a significant amount of electricity, further increasing energy consumption and load on the power grid. Therefore, there is an urgent need to develop low-energy and sustainable cooling technologies for power equipment. In this study, a hybrid passive cooling composite designed to enhance heat dissipation for heavy-load power equipment is introduced. Specifically, the composite material achieves outstanding radiative cooling performance with an average solar reflectance of up to 0.98, while its excellent atmospheric water harvesting performance ensures high evaporation cooling power without the need for manual water replenishment. As a result, the composite effectively lowers the temperature of outdoor heavy-load power equipment (e.g., transformers) by 25.3 °C. The excellent heat dissipation properties of the composite make it a powerful tool in safeguarding electrical systems.

Research on the safety risks of microwave irradiation on motion balance perception in electric power environments.

To the microwave irradiation safety hazards caused by the co-construction of towers in smart grids, this paper investigates the effects of microwave irradiation in the power environment on the biological motion balance perception function. Firstly, simulation of microwave signals in the electric power environment, i.e., low-frequency harmonics and high-frequency carriers, were realized by signal modulation and applied in four types of behavior testing scenarios. Then, determining rats as target organisms to replace workers and randomly dividing into groups in proportion: open field, rotating rod fatigue, beam walking and forced swimming. Configuring radar with various parameters to match the electric power irradiation scene and stimulate rats, monitoring the abnormal behavior by image processing module, including posture, motion trajectory, distance, and other features. The experimental result showed that exposed to microwaves induce rats motor ability decline, balance perception imbalance, together with paralysis within long-term exposure, and its locomotor activity, coordination, posture control and reaction time all exhibit varying degrees of weakening. These findings indicate that microwave irradiation in electric power environment may pose significant health and safety risks for worker.

Modulation of the magnetic properties of mononuclear Dy(III) complexes by tuning the coordination geometry and local symmetry.

Precise control of the crystal field and local symmetry around the paramagnetic spin center is crucial for the design and synthesis of single-molecule magnets (SMMs). Herein, three mononuclear Dy(III)-based complexes, [Dy(LN6)(CH3COO)2](BPh4)(CH2Cl2) (1), [Dy(LN6)(2,6-Cl-4-NO2-PhO)(H2O)2]2(PF6)2(H2O)(2,6-Cl-4-NO2-PhO)2 (2) and [Dy(LN6)(2,6-Cl-4-NO2-PhO)2](BPh4)(CH2Cl2)2 (3) (LN6 = N6-hexagonal plane accomplished by a neutral Schiff base ligand formed from 2,6-diacetylpyridine and ethylenediamine), are successfully isolated. In these complexes, the Dy(III) centers are coordinated with six neutral N atoms from a nonrigid equatorial ligand, while different oxygen-bearing ligands are arranged at the axial positions of the central ions by gradual regularization of the axial ligands. As a result, Dy(III) ions in the three complexes exhibit various coordination geometries, forming a ten-coordinate tetradecahedron for 1, a nine-coordinate muffin configuration for 2 and a distorted eight-coordinate hexagonal bipyramid for 3. Magnetic studies reveal that all complexes exhibit no SIM behaviour under zero dc field, due to the predominant quantum tunneling of magnetization (QTM), which can be effectively suppressed by additional dc fields. Experiments, coupled with theoretical calculations, demonstrate that varying local symmetries and coordination geometries are synergistically responsible for the disparities of QTM and uniaxial anisotropy, resulting in notably different magnetic properties.

Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aß and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology.

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimers disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprograming with an increase in glycolysis and impaired uptake of Aß. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aß; plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to take up Aß; such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

Targeting treatment resistance: unveiling the potential of RNA methylation regulators and TG-101,209 in pan-cancer neoadjuvant therapy.

BACKGROUND: Tumor recurrence and mortality rates remain challenging in cancer patients despite comprehensive treatment. Neoadjuvant chemotherapy and immunotherapy aim to eliminate residual tumor cells, reducing the risk of recurrence. However, drug resistance during neoadjuvant therapy is a significant hurdle. Recent studies suggest a correlation between RNA methylation regulators (RMRs) and response to neoadjuvant therapy. METHODS: Using a multi-center approach, we integrated advanced techniques such as single-cell transcriptomics, whole-genome sequencing, RNA sequencing, proteomics, machine learning, and in vivo/in vitro experiments. Analyzing pan-cancer cohorts, the association between neoadjuvant chemotherapy/immunotherapy effectiveness and RNA methylation using single-cell sequencing was investigated. Multi-omics analysis and machine learning algorithms identified genomic variations, transcriptional dysregulation, and prognostic relevance of RMRs, revealing distinct molecular subtypes guiding pan-cancer neoadjuvant therapy stratification. RESULTS: Our analysis unveiled a strong link between neoadjuvant therapy efficacy and RNA methylation dynamics, supported by pan-cancer single-cell sequencing data. Integration of omics data and machine learning algorithms identified RMR genomic variations, transcriptional dysregulation, and prognostic implications in pan-cancer. High-RMR-expressing tumors displayed increased genomic alterations, an immunosuppressive microenvironment, poorer prognosis, and resistance to neoadjuvant therapy. Molecular investigations and in vivo/in vitro experiments have substantiated that the JAK inhibitor TG-101,209 exerts notable effects on the immune microenvironment of tumors, rendering high-RMR-expressing pan-cancer tumors, particularly in pancreatic cancer, more susceptible to chemotherapy and immunotherapy. CONCLUSIONS: This study emphasizes the pivotal role of RMRs in pan-cancer neoadjuvant therapy, serving as predictive biomarkers for monitoring the tumor microenvironment, patient prognosis, and therapeutic response. Distinct molecular subtypes of RMRs aid individualized stratification in neoadjuvant therapy. Combining TG-101,209 adjuvant therapy presents a promising strategy to enhance the sensitivity of high-RMR-expressing tumors to chemotherapy and immunotherapy. However, further validation studies are necessary to fully understand the clinical utility of RNA methylation regulators and their impact on patient outcomes.

Boosting Reactive Oxygen Species Generation via Contact-Electro-Catalysis with FeIII-Initiated Self-cycled Fenton System.

Contact Electro-Catalysis (CEC) using commercial dielectric materials in contact-separation cycles with water triggers interfacial electron transfer, generating reactive oxygen species (ROS). However, the hydrophobicity of these materials limits reaction sites, and the generated ROS often combine to form hydrogen peroxide (H2O2), which does not decompose further, leading to suboptimal rates. Addressing H2O2 generation and activation is crucial for advancing CEC. Here, we synthesized a catalyst by loading polytetrafluoroethylene (PTFE) onto ZSM-5 (PZ), achieving uniform dispersion in water. Introducing an FeIII-initiated self-cycling Fenton system (SF-CEC), with synergistic O2 activation and FeIII-activated H2O2, enhanced ROS generation. This system enabled nearly 99% degradation of azo dyes within 10 minutes, a sixfold improvement over traditional CEC. It represents the fastest ultrasound-induced degradation rate of methyl orange dye to date. Without extra oxidants, it also achieved stable dissolution of precious metals in weakly acidic solutions at room temperature, with 80% gold dissolution within 2 hours-2.5 times faster than similar systems. This study corrects the perception of CEC under acidic conditions, offering new insights for dye degradation and precious metal recovery.

Dissecting negative effects of two root-associated bacteria on the growth of an invasive weed.

Plant-associated microorganisms can negatively influence plant growth, which makes them potential biocontrol agents for weeds. Two Gammaproteobacteria, Serratia plymuthica and Pseudomonas brassicacearum, isolated from roots of Jacobaea vulgaris, an invasive weed, negatively affect its root growth. We examined whether the effects of S. plymuthica and P. brassicacearum on J. vulgaris through root inoculation are concentration-dependent and investigated if these effects were mediated by metabolites in bacterial suspensions. We also tested whether the two bacteria negatively affected seed germination and seedling growth through volatile emissions. Lastly, we investigated the host specificity of these two bacteria on nine other plant species. Both bacteria significantly reduced J. vulgaris root growth after root inoculation, with S. plymuthica showing a concentration-dependent pattern in vitro. The cell-free supernatants of both bacteria did not affect J. vulgaris root growth. Both bacteria inhibited J. vulgaris seed germination and seedling growth via volatiles, displaying distinct volatile profiles. However, these negative effects were not specific to J. vulgaris. Both bacteria negatively affect J. vulgaris through root inoculation via the activity of bacterial cells, while also producing volatiles that hinder J. vulgaris germination and seedling growth. However, their negative effects extend to other plant species, limiting their potential for weed control.

Myc-mediated inhibition of HIF1a degradation promotes M2 macrophage polarization and impairs CD8 T cell function through lactic acid secretion in ovarian cancer.

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132-/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132-/- mice, shedding light on potential therapeutic avenues for ovarian cancer management.

miR-1290 induces endothelial-to-mesenchymal transition and promotes vascular restenosis after angioplasty by targeting FGF2.

BACKGROUND AND AIMS: Endothelial-to-mesenchymal transition (EndMT) is an important reason for restenosis but the underlying mechanisms need to be further explored. Therefore, the purpose of this study is to screen significantly different microRNAs (miRNAs) and assess their functions and downstream pathways. METHODS: This study screened several miRNAs with significant differences between human arterial segments from restenosis patients and healthy volunteers using whole transcriptome resequencing and real-time quantitative reverse transcription PCR (qRT-PCR). We explored the correlation between miR-1290 and EndMT using Western blot, qRT-PCR, Pearson correlation analysis and further functional gain and loss experiments. Subsequently, we identified the direct downstream target of miR-1290 by bioinformatics analysis, RNA pull-down, double Luciferase reporter gene and other functional experiments. Finally, rat carotid artery balloon injury model demonstrated the therapeutic potential of miR-1290 regulator. RESULTS: We screened 129 differentially expressed miRNAs. Among them, miR-1290 levels were significantly higher in restenosis arteries than in healthy arteries, and as expected, EndMT was functionally enhanced with miR-1290 overexpression and comparatively weakened when miR-1290 was knocked down. In addition, fibroblast growth factor-2 (FGF2) was established as the downstream target of miR-1290. Finally, we utilized an animal model and found that low miR-1290 levels could alleviate EndMT and the progression of restenosis. CONCLUSIONS: Our study demonstrated the strong regulatory effects of miR-1290 on EndMT, endometrial hyperplasia and restenosis, which could be useful as biomarker and therapeutic target for stent implantation in patients with arterial occlusive disease of the lower extremities.

Modified buried vertical mattress suture technique for excisional suturing of benign parotid tumors: A retrospective study.

AIM: The purpose of this retrospective patient chart review was to analyze the clinical data of 52 patients with benign parotid tumors who underwent modified buried vertical mattress sutures and to assess the postoperative complication rate and patient scarring. METHODS: A total of 52 patients with benign parotid tumors underwent total parotidectomy and modified buried vertical mattress suture. Variables included general characteristics (age, gender, tumor diameter, and pathologic type), surgical indicators (suture time, wound healing time, operative time, hospital stay, bleeding volume, and drainage volume), complication rates, and Sunnybrook facial neurological function score, visual scar scale (VSS) score and patient and observer scar assessment scale (POSAS) score. RESULTS: Most tumors were less than 3 cm in diameter, with pleomorphic adenomas being the most common. Suture time was 14.83 ± 1.61 min, operative time was 58.90 ± 15.76 min and hospital stay were 5.12 ± 0.96 days. Postoperatively, salivary fistulae developed in one patient, Frey's syndrome in two patients, temporary facial paralysis in six patients and temporary numbness in the incision area in six patients. At 6 months postoperatively, 86.5% of patients had a Sunnybrook score of more than 80, and VSS scores and POSAS scores were between one and two. CONCLUSION: The postoperative complication rate was 30.8%, and the scarring in the facial incision area was mild and close to normal skin at 3 years postoperatively.

Challenges and Perspectives of Environmental Catalysis for NO x Reduction.

Environmental catalysis has attracted great interest in air and water purification. Selective catalytic reduction with ammonia (NH3-SCR) as a representative technology of environmental catalysis is of significance to the elimination of nitrogen oxides (NO x ) emitting from stationary and mobile sources. However, the evolving energy landscape in the nonelectric sector and the changing nature of fuel in motor vehicles present new challenges for NO x catalytic purification over the traditional NH3-SCR catalysts. These challenges primarily revolve around the application limitations of conventional industrial NH3-SCR catalysts, such as V2O5-WO3(MoO3)/TiO2 and chabazite (CHA) structured zeolites, in meeting both the severe requirements of high activity at ultralow temperatures and robust resistance to the wide array of poisons (SO2, HCl, phosphorus, alkali metals, and heavy metals, etc.) existing in more complex operating conditions of new application scenarios. Additionally, volatile organic compounds (VOCs) coexisting with NO x in exhaust gas has emerged as a critical factor further impeding the highly efficient reduction of NO x . Therefore, confronting the challenges inherent in current NH3-SCR technology and drawing from the established NH3-SCR reaction mechanisms, we discern that the strategic manipulation of the properties of surface acidity and redox over NH3-SCR catalysts constitutes an important pathway for increasing the catalytic efficiency at low temperatures. Concurrently, the establishment of protective sites and confined structures combined with the strategies for triggering antagonistic effects emerge as imperative items for strengthening the antipoisoning potentials of NH3-SCR catalysts. Finally, we contemplate the essential status of selective synergistic catalytic elimination technology for abating NO x and VOCs. By virtue of these discussions, we aim to offer a series of innovative guiding perspectives for the further advancement of environmental catalysis technology for the highly efficient NO x catalytic purification from nonelectric industries and motor vehicles.

Effects of Exercise on the Inter-Session Accuracy of sEMG-Based Hand Gesture Recognition.

Surface electromyography (sEMG) is commonly used as an interface in human-machine interaction systems due to their high signal-to-noise ratio and easy acquisition. It can intuitively reflect motion intentions of users, thus is widely applied in gesture recognition systems. However, wearable sEMG-based gesture recognition systems are susceptible to changes in environmental noise, electrode placement, and physiological characteristics. This could result in significant performance degradation of the model in inter-session scenarios, bringing a poor experience to users. Currently, for noise from environmental changes and electrode shifting from wearing variety, numerous studies have proposed various data-augmentation methods and highly generalized networks to improve inter-session gesture recognition accuracy. However, few studies have considered the impact of individual physiological states. In this study, we assumed that user exercise could cause changes in muscle conditions, leading to variations in sEMG features and subsequently affecting the recognition accuracy of model. To verify our hypothesis, we collected sEMG data from 12 participants performing the same gesture tasks before and after exercise, and then used Linear Discriminant Analysis (LDA) for gesture classification. For the non-exercise group, the inter-session accuracy declined only by 2.86%, whereas that of the exercise group decreased by 13.53%. This finding proves that exercise is indeed a critical factor contributing to the decline in inter-session model performance.

Ultrasensitive Electrochemiluminescence Biosensor Based on DNA-Bio-Bar-Code and Hybridization Chain Reaction Dual Signal Amplification for Exosomes Detection.

Exosomes have received considerable attention as potent reference markers for the diagnosis of various neoplasms due to their close and direct relationship with the proliferation, adhesion, and migration of tumor. The ultrasensitive detection of cancer-derived low-abundance exosomes is imperative, but still a great challenge. Herein, we report an electrochemiluminescence (ECL) biosensor based on the DNA-bio-bar-code and hybridization chain reaction (HCR)-mediated dual signal amplification for the ultrasensitive detection of cancer-derived exosomes. In this system, two types of aptamers were modified on the magnetic nanoprobe (MNPs) and gold nanoparticles (AuNPs) with numerous bio-bar-code DNA, respectively, which formed "sandwich" structures in the presence of specific target exosomes. The "sandwich" structures were separated under magnetic field, and the numerous bio-bar-code DNA were released by dissolving AuNPs. The released bio-bar-code DNA triggered the HCR procedure to produce a good deal of long DNA duplex structure for embedding in hemin, which generated strong ECL signal in the presence of coreactors for ultrasensitive detection of exosomes. Under the optimal conditions, it exhibited a good linearly of exosomes ranging from 10 to 104 exosomes particle µL-1 with limit of detection down to 5.01 exosome particle µL-1. Furthermore, the high ratio of ECL signal and minor change of ECL intensity indicated the good specificity, stability, and repeatability of this ECL biosensor. Given the good performance for exosome analysis, this ultrasensitive ECL biosensor has a promising application in the clinical diagnosis of early cancers.

The role of the SIRT1/NF-κB/NLRP3 pathway in the pyroptosis of lens epithelial cells under shortwave blue light radiation.

Cataracts are the world's number one blinding eye disease. Cataracts can only be effectively treated surgically, although there is a chance of surgical complications. One of the pathogenic processes of cataracts is oxidative stress, which closely correlated with pyroptosis. SIRT1 is essential for the regulation of pyroptosis. Nevertheless, the role of SIRT1 in formation of cataracts is unclear. In this work, we developed an in vitro model of shortwave blue light (SWBL)-induced scotomization in human lens epithelial cells (HLECs) and an in vivo model of SWBL-induced cataracts in rats. The study aimed to understand how the SIRT1/NF-κB/NLRP3 pathway functions. Additionally, the evaluation included cell death and the release of lactate dehydrogenase (LDH), a cytotoxicity marker, from injured cells. First, we discovered that SWBL exposure resulted in lens clouding in Sprague- Dawley (SD) rats and that the degree of clouding was positively linked to the duration of irradiation. Second, we discovered that SIRT1 exhibited antioxidant properties and was connected to the NF-κB/NLRP3 pathway. SWBL irradiation inhibited SIRT1 expression, exacerbated oxidative stress, and promoted nuclear translocation of NF-κB and the activation of the NLRP3 inflammasome, which caused LEC pyroptosis and ultimately led to cataract formation. Transient transfection to increase the expression of SIRT1 decreased the protein expression levels of NF-κB, NLRP3, caspase-1, and GSDMD, inhibited HLEC pyroptosis, and reduced the release of LDH, providing a potential method for cataract prevention and treatment.

Black Phosphorus Nanosheets-Based Hydrogel for Efficient Bacterial Inhibition and Accelerating Wound Healing.

With the swift evolution of multidrug-resistant bacteria resulting from the intense and inappropriate use of antibiotics, there is a pressing need for innovative solutions. In this study, a thermosensitive hydrogel was developed for efficient bacterial inhibition and promotion of wound healing. The antibacterial chitosan (CS) thermosensitive hydrogel, cross-linked with two-dimensional photothermal nanomaterial black phosphorus (BP) nanosheets through electrostatic interactions, effectively encapsulates and sustains the release of angiogenic drug deferoxamine mesylate (DFO). This facilitates the acceleration of re-epithelialization and neovascularization by enhancing cell migration and proliferation. Following near-infrared (NIR) treatment, this hydrogel demonstrates rapid eradication of the most common multidrug-resistant bacteria encountered in clinical settings, achieved through physical disruption of bacterial membranes and photothermal therapies. Noteworthy is the significant upregulation of IL-19 expression via STAT3 signaling pathways by the BP/CS-DFO hydrogel in a full-thickness wound model. This results in the polarization of the anti-inflammatory M2 macrophage phenotype, altering the microenvironment to a pro-healing state and enhancing extracellular matrix deposition and blood vessel formation. In conclusion, the BP/CS-DFO hydrogel shows immense promise as a potential clinical candidate for wound healing and antimicrobial therapy. Its innovative design and multifunctional capabilities position it as a valuable asset in combating antibiotic resistance and enhancing efficiency in wound healing.

Cilofexor in Patients With Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: An Open-Label Phase 1B Study.

INTRODUCTION: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

Bitopic Ligands Support the Presence of a Metastable Binding Site at the ß2 Adrenergic Receptor.

Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands (1-4) were designed by molecular docking of (S)-alprenolol ((S)-ALP) in the cocrystal structure of the ß2 adrenergic receptor (ß2AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to (S)-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the ß2AR. This ligand design principle can find applications beyond the ß2AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.

Epidemiology and first aid measures in pediatric burn patients in northern China during 2016-2020: A single-center retrospective study.

Background and Aims: Burn and scald injuries are the fourth most common type of trauma. Pediatric burns account for a high proportion of the total number of burn patients and impose a high burden on public health. Understanding the epidemiology of pediatric burns can help improve science education and reduce the incidence of burn injuries. Methods: This study is a single-center retrospective study. One thousand five hundred and twenty-seven pediatric burn patients admitted to our burn center from January 2016 to December 2020 were included. Demographic and epidemiological data of included patients were extracted and analyzed. The correlations of categorical data were tested by the Chi-square tests, and differences of continuous data were tested by the Kruskal-Wallis tests. A p-value of less than 0.05 was considered to be statistically significant. Results: The results showed that children under 3 years of age were most susceptible to burn and scald injuries. Burn injuries were most likely to occur in the season of winter and at the place of home. 56.6% of included patients did receive first aid measures, while 1.8% received gold-standard first aid. Clinical variables related to the severity of injuries were statistically different between patients with and without cooling measures in first aid. Linear regression models showed that emergency treatment of burns in children and adolescents was associated with outcome indicators, including number of operations, total operation duration per total burn surface area (TBSA), cost per TBSA, and length of stay per TBSA. Conclusions: This study summarized the epidemiology and outcomes of pediatric burn patients admitted to a burn center in northern China. Adopting cooling measures in first aid can reduce the severity of injuries and reduce the burden on the medical system. Education on burn prevention and first aid measures to caregivers of children, especially preschool children, should be strengthened.

Molecular Mechanism of the ß3AR Agonist Activity of a ß-Blocker.

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three ß-adrenergic receptors (ßARs). The ß3AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of ß1AR and ß2AR. Interestingly, several ß-blockers, which are antagonists of the ß1ARs and ß2ARs, have been reported to exhibit agonist activity at the ß3AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of ß3AR agonist drugs with improved selectivity and reduced off-target effects. In this work, we determined the structures of human ß3AR in complex with the endogenous agonist epinephrine or with a synthetic ß3AR agonist carazolol, which is also a high-affinity ß-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D3.32 directly contribute to carazolol's distinct activities as an antagonist for the ß2AR and an agonist for the ß3AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective ß3AR agonists, paving the way for new therapeutic opportunities.