Catastrophic Cognition Is a Stronger Predictor Than Emotional Factors of Acute Postoperative Pain in Patients With Traumatic Orthopedic Injuries.

BACKGROUND: Both cognitive (pain catastrophizing [PC]) and emotional factors (anxiety, depression, and optimism) play vital roles in acute postoperative pain (APOP) management among patients with traumatic orthopedic injuries (TOIs). It remains uncertain if these psychological factors independently or collectively impact APOP in patients with TOIs, and the underlying mechanisms by which various psychological factors impact APOP in patients with TOIs are also ambiguous. PURPOSE: The aims of the current research were to analyze the effects of PC and emotional factors (anxiety, depression, and optimism) on APOP in patients with TOIs and explore the potential mechanisms by which PC and emotional factors influence APOP based on a hypothetical moderated mediation pathway mediated by pain-related fear. METHODS: This was an observational cross-sectional study. RESULTS: PC was a significantly positive predictor of APOP regardless of coexistence with emotional factors. TOI patients who had higher PC had more severe APOP (ß = 0.57, standard error [SE] = 0.005, p < .01, adjusted R2 = 0.78; ß = 0.84, SE = 0.003, p < .01, adjusted R2 = 0.77, respectively). Furthermore, when positive and negative emotions coexisted (adjusted R2 = 0.74), anxiety levels were a significant positive predictor of APOP (ß = 0.71, SE = 0.009, p < .01) and optimism was a significant negative predictor of APOP (ß = -0.24, SE = 0.008, p < .01). Pain-related fear played a mediating role in the association between the level of PC (effect = 0.044, 95% confidence interval [CI] = 0.027 to 0.062), anxiety (effect = 0.102, 95% CI = 0.075 to 0.137), and APOP in patients with TOIs. Optimism moderated the strength of the relationship between PC (95% CI = -0.020 to -0.010), anxiety (95% CI = -0.045 to -0.003), and APOP mediated by pain-related fear. CONCLUSIONS: Clinical staff should assess the level of PC and emotional factors to identify TOI patients at high risk for APOP, subsequently facilitating the optimization of pain management and efficient utilization of nursing resources through early discussion.

Single-cell multiomics analysis reveals cell/tissue-specific associations in bipolar disorder.

This study investigates the cellular origin and tissue heterogeneity in bipolar disorder (BD) by integrating multiomics data. Four distinct datasets were employed, including single-cell RNA sequencing (scRNA-seq) data (embryonic and fetal brain, n = 8, 1,266 cells), BD Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data (adult brain, n = 210), BD bulk RNA-seq data (adult brain, n = 314), and BD genome-wide association study (GWAS) summary data (n = 413,466). The integration of scRNA-seq data with multiomics data relevant to BD was accomplished using the single-cell disease relevance score (scDRS) algorithm. We have identified a novel brain cell cluster named ADCY1, which exhibits distinct genetic characteristics. From a high-resolution genetic perspective, glial cells emerge as the primary cytopathology associated with BD. Specifically, astrocytes were significantly related to BD at the RNA-seq level, while microglia showed a strong association with BD across multiple panels, including the transcriptome-wide association study (TWAS), ATAC-seq, and RNA-seq. Additionally, oligodendrocyte precursor cells displayed a significant association with BD in both ATAC-seq and RNA-seq panel. Notably, our investigation of brain regions affected by BD revealed significant associations between BD and all three types of glial cells in the dorsolateral prefrontal cortex (DLPFC). Through comprehensive analyses, we identified several BD-associated genes, including CRMP1, SYT4, UCHL1, and ZBTB18. In conclusion, our findings suggest that glial cells, particularly in specific brain regions such as the DLPFC, may play a significant role in the pathogenesis of BD. The integration of multiomics data has provided valuable insights into the etiology of BD, shedding light on potential mechanisms underlying this complex psychiatric disorder.

SFC active reconfiguration based on user mobility and resource demand prediction in dynamic IoT-MEC networks.

To achieve secure, reliable, and scalable traffic delivery, request streams in mobile Internet of Things (IoT) networks supporting Multi-access Edge Computing (MEC) typically need to pass through a service function chain (SFC) consisting of an ordered series of Virtual Network Functions (VNFs), and then arrive at the target application in the MEC for processing. The high mobility of users and the real-time variability of network traffic in IoT-MEC networks lead to constant changes in the network state, which results in a mismatch between the performance requirements of the currently deployed SFCs and the allocated resources. Meanwhile, there are usually multiple instances of the same VNF in the network, and proactively reconfiguring the deployed SFCs based on the network state changes to ensure high quality of service in the network is a great challenge. In this paper, we study the SFC Reconfiguration Strategy (SFC-RS) based on user mobility and resource demand prediction in IoT MEC networks, aiming to minimize the end-to-end delay and reconfiguration cost of SFCs. First, we model SFC-RS as Integer Linear Programming (ILP). Then, a user trajectory prediction model based on codec movement with attention mechanism and a VNF resource demand prediction model based on the Long Short-Term Memory (LSTM) network are designed to accurately predict user trajectories and node computational and storage resources, respectively. Based on the prediction results, a Prediction-based SFV Active Reconfiguration (PSAR) algorithm is proposed to achieve seamless SFC migration and routing update before the user experience quality degrades, ensuring network consistency and high quality service. Simulation results show that PSAR provides 51.28%, 28.60%, 21.75%, and 16.80% performance improvement over the existing TSRFCM, DDQ, OSA, and DPSM algorithms in terms of end-to-end delay reduction, and 33.32%, 18.94%, 67.42%, and 60.61% performance optimization in terms of reconfiguration cost reduction.

Mesoporous silica thin film as effective coating for enhancing osteogenesis through selective proteins adsorption and blood clotting.

The role of blood clot in tissue repair has been identified for a long time whereas its participation in the integration between implants and host tissues has attracted attentions only in recent years. In this work, the mesoporous silica thin film (MSTF) with either vertical or parallel orientation was deposited on titania nanotubes (TNT) surface, resulting in superhydrophilic nanoporous surfaces. Through proteomic analysis of blood plasma adsorption, the MSTF coating could significantly increase the acidic proteins abundance and the coagulation factors (XII and XI) adsorption, with the help of cations (Na+, Ca2+) binding. As a consequent, both platelets activation and the blood clot formation were significantly enhanced on MSTF surface with more condensed fibrin networks. Two classical growth factors of PDGF-AB and TGF-ß were enriched in the blood clots from MSTF surface, which accounted for robust osteogenesis both in vitro and in vivo. In conclusion, the study demonstrates that the MSTF may be a promising coating to enhance osteogenesis through modulating blood clot formation.

Online learning fuzzy echo state network with applications on redundant manipulators.

Redundant manipulators are universally employed to save manpower and improve work efficiency in numerous areas. Nevertheless, the redundancy makes the inverse kinematics of manipulators hard to address, thus increasing the difficulty in instructing manipulators to perform a given task. To deal with this problem, an online learning fuzzy echo state network (OLFESN) is proposed in the first place, which is based upon an online learning echo state network and the Takagi-Sugeno-Kang fuzzy inference system (FIS). Then, an OLFESN-based control scheme is devised to implement the efficient control of redundant manipulators. Furthermore, simulations and experiments on redundant manipulators, covering UR5 and Franka Emika Panda manipulators, are carried out to verify the effectiveness of the proposed control scheme.

Intensive care of a patient undergoing combined multi-organ cluster ("larynx-trachea-thyroid-hypopharynx-esophagus") transplantation: A case report.

OBJECTIVE: The aim of this study was to summarize the intensive care experience of a patient undergoing combined multi-organ cluster ("larynx-trachea-thyroid-hypopharynx-esophagus") transplantation. METHODS: The intensive care management plan for this case was developed by a multidisciplinary team, with focus on 6 aspects: (1) stabilizing the circulation and reducing anastomotic tension by position management to improve the survival chances of transplanted organs, (2) adopting goal-directed analgesia and sedation protocols, as well as preventing anastomotic fistula, (3) implementing a bedside ultrasound-guided nutrition plan, (4) employing "body-mind" synchronous rehabilitation to facilitate functional recovery, (5) taking antirejection treatment and protective isolation measures, (6) monitoring and nursing thyroid function. RESULTS: During the intensive care, the patient's vital signs were stable. The patient was successfully weaned from the ventilator and transferred to the general ward for further treatment at 9 days postoperatively, and discharged upon recovery at 58 days postoperatively. The patient was in good condition during follow-up. CONCLUSION: This study provides reference for the care of patients who undergo similar transplantation in the future.

Cancer-associated fibroblasts-secreted exosomal miR-92a-3p promotes tumor growth and stemness in hepatocellular carcinoma through activation of Wnt/ß-catenin signaling pathway by suppressing AXIN1.

Cancer-associated fibroblasts (CAFs) are a major cellular component in the tumor microenvironment and have been shown to exhibit protumorigenic effects in hepatocellular carcinoma (HCC). This study aimed to delve into the mechanisms underlying the tumor-promoting effects of CAFs in HCC. Small RNA sequencing was conducted to screen differential expressed microRNAs in exosomes derived from CAFs and normal fibroblasts (NFs). The miR-92a-3p expression was then measured using reverse transcriptase quantitative real-time PCR in CAFs, NFs, CAFs-derived exosomes (CAFs-Exo), and NF-derived exosomes (NFs-Exo). Compared to NFs or NF-Exo, CAFs and CAFs-Exo significantly promoted HCC cell proliferation, migration, and stemness. Additionally, compared to NFs or NF-Exo, miR-92a-3p level was notably higher in CAFs and CAFs-Exo, respectively. Exosomal miR-92a-3p was found to enhance HCC cell proliferation, migration, and stemness. Meanwhile, AXIN1 was targeted by miR-92a-3p. Exosomal miR-92a-3p could activate ß-catenin/CD44 signaling in HCC cells by inhibiting AXIN1 messenger RNA. Furthermore, in vivo studies verified that exosomal miR-92a-3p notably promoted tumor growth and stemness through targeting AXIN1/ß-catenin axis. Collectively, CAFs secreted exosomal miR-92a-3p was capable of promoting growth and stemness in HCC through activation of Wnt/ß-catenin signaling pathway by suppressing AXIN1. Therefore, targeting CAFs-derived miR-92a-3p may be a potential strategy for treating HCC.

Plasma metabolites and inflammatory proteins profiling predict outcome of Fufang Duzhong Jiangu granules treating Kashin-Beck disease.

To investigate predictive biomarkers that could be used to identify patients' response to treatment, plasma metabolomics and proteomics analyses were performed in Kashin-Beck disease (KBD) patients treated with Fufang Duzhong Jiangu Granules (FDJG). Plasma was collected from 12 KBD patients before treatment and 1 month after FDJG treatment. LC-MS and olink proteomics were employed for obtaining plasma metabolomics profiling and inflammatory protein profiles. Patients were classified into responders and non-responders based on drug efficacy. Enrichment analyses of differential metabolites and proteins of the responders at baseline and after treatment were conducted to study the mechanism of drug action. Differential metabolites and proteins between the two groups were screened as biomarkers to predict the drug efficacy. The receiver operating characteristic curve was used to evaluate the prediction accuracy of biomarkers. The changes in metabolites and inflammatory proteins in responders after treatment reflected the mechanism of FDJG treatment for KBD, which may act on glycerophospholipid metabolism, d-glutamine and d-glutamate metabolism, nitrogen metabolism and NF-kappa B signaling pathway. Three metabolites were identified as potential predictors: N-undecanoylglycine, ß-aminopropionitrile and PC [18:3(6Z,9Z,12Z)/20:4(8Z,11Z,14Z,17Z)]. For inflammatory protein, interleukin-8 was identified as a predictive biomarker to detect responders. Combined use of these four biomarkers had high predictive ability (area under the curve = 0.972).

Control of Hybrid Exciton Lifetime in MoSe2/WS2 Moiré Heterostructures.

Hybrid excitons, characterized by their strong oscillation strength and long lifetimes, hold great potential as information carriers in semiconductors. They offer promising applications in exciton-based devices and circuits. MoSe2/WS2 heterostructures represent an ideal platform for studying hybrid excitons, but how to regulate the exciton lifetime has not yet been explored. In this study, layer hybridization is modulated by applying electric fields parallel or antiparallel to the dipole moment, enabling us to regulate the exciton lifetime from 1.36 to 4.60 ns. Furthermore, the time-resolved photoluminescence decay traces are measured at different excitation power. A hybrid exciton annihilation rate of 8.9 × 10-4 cm2 s-1 is obtained by fitting. This work reveals the effects of electric fields and excitation power on the lifetime of hybrid excitons in MoSe2/WS2 1.5° moiré heterostructures, which play important roles in high photoluminescence quantum yield optoelectronic devices based on transition-metal dichalcogenides heterostructures.

Multi-scale DNA language model improves 6 mA binding sites prediction.

DNA methylation at the N6 position of adenine (N6-methyladenine, 6 mA), which refers to the attachment of a methyl group to the N6 site of the adenine (A) of DNA, is an important epigenetic modification in prokaryotic and eukaryotic genomes. Accurately predicting the 6 mA binding sites can provide crucial insights into gene regulation, DNA repair, disease development and so on. Wet experiments are commonly used for analyzing 6 mA binding sites. However, they suffer from high cost and expensive time. Therefore, various deep learning methods have been widely used to predict 6 mA binding sites recently. In this study, we develop a framework based on multi-scale DNA language model named "iDNA6mA-MDL". "iDNA6mA-MDL" integrates multiple kmers and the nucleotide property and frequency method for feature embedding, which can capture a full range of DNA sequence context information. At the prediction stage, it also leverages DNABERT to compensate for the incomplete capture of global DNA information. Experiments show that our framework obtains average AUC of 0.981 on a classic 6 mA rice gene dataset, going beyond all existing advanced models under fivefold cross-validations. Moreover, "iDNA6mA-MDL" outperforms most of the popular state-of-the-art methods on another 11 6 mA datasets, demonstrating its effectiveness in 6 mA binding sites prediction.

Addition of operative hysteroscopy to vacuum aspiration for the management of early pregnancy loss after in vitro fertilization.

OBJECTIVE: To investigate whether operative hysteroscopy in addition to vacuum aspiration for the management of early pregnancy loss effectively increases the success rate of subsequent frozen embryo transfer. DESIGN: Propensity score-matched cohort study. SUBJECTS: Women with a miscarriage at 5 to 16 gestational weeks during an IVF cycle in Peking University Third Hospital from 2015 to 2022. EXPOSURE: Hysteroscopy plus vacuum aspiration versus conventional vacuum aspiration. MAIN OUTCOME MEASURES: Live birth rate in the subsequent frozen embryo transfer. RESULTS: 347 women who underwent vacuum aspiration plus hysteroscopy and 2,562 women who underwent conventional vacuum aspiration were included in the analysis. After propensity score matching (1:1 ratio), 325 women were included in each group. Compared to women who underwent vacuum aspiration, those who underwent vacuum aspiration plus hysteroscopy were associated with a lower rate of live birth in the propensity-based matched cohort (22% vs 30%, aOR = 0.68 (0.47, 0.97)). Biochemical, clinical and multiple pregnancy rates were not significantly different, as was miscarriage rate. In the overall cohort, 11 women experienced surgery reintervention in the vacuum aspiration group (0.4%), while no one required surgery reintervention in the vacuum aspiration plus hysteroscopy group. CONCLUSION: Women who underwent vacuum aspiration plus hysteroscopy might be associated with lower rates of live birth compared to those who underwent vacuum aspiration. Further studies are necessary to establish this relationship definitively.

The Biosynthesis Process of Small RNA and Its Pivotal Roles in Plant Development.

In the realm of plant biology, small RNAs (sRNAs) are imperative in the orchestration of gene expression, playing pivotal roles across a spectrum of developmental sequences and responses to environmental stressors. The biosynthetic cascade of sRNAs is characterized by an elaborate network of enzymatic pathways that meticulously process double-stranded RNA (dsRNA) precursors into sRNA molecules, typically 20 to 30 nucleotides in length. These sRNAs, chiefly microRNAs (miRNAs) and small interfering RNAs (siRNAs), are integral in guiding the RNA-induced silencing complex (RISC) to selectively target messenger RNAs (mRNAs) for post-transcriptional modulation. This regulation is achieved either through the targeted cleavage or the suppression of translational efficiency of the mRNAs. In plant development, sRNAs are integral to the modulation of key pathways that govern growth patterns, organ differentiation, and developmental timing. The biogenesis of sRNA itself is a fine-tuned process, beginning with transcription and proceeding through a series of processing steps involving Dicer-like enzymes and RNA-binding proteins. Recent advances in the field have illuminated the complex processes underlying the generation and function of small RNAs (sRNAs), including the identification of new sRNA categories and the clarification of their involvement in the intercommunication among diverse regulatory pathways. This review endeavors to evaluate the contemporary comprehension of sRNA biosynthesis and to underscore the pivotal role these molecules play in directing the intricate performance of plant developmental processes.

Characteristics of Umami Taste of Soy Sauce Using Electronic Tongue, Amino Acid Analyzer, and MALDI-TOF MS.

The objective of this study was to investigate the umami characteristics of soy sauce using electronic tongue evaluation and amino acid composition and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis. The soy sauce peptides were isolated from soy sauce using XAD-16 macroporous resin combined with ethanol solution. The results showed that the soy sauce peptide fraction eluted by 60% ethanol (SS-60%) exhibited a prominent umami taste, and the umami scores were highly positively correlated with the amino acid nitrogen contents of soy sauces. The umami scores of SS-60% were significantly positively correlated with the contents of free amino acids. Especially, Phe showed the highest positive correlation with the umami scores. In addition, five characteristic ion peaks with m/z at 499, 561, 643, 649, and 855 were identified in the peptide mass fingerprinting. Therefore, this study provides new insights into the umami characteristics for the taste evaluation and reality identification of soy sauce.

Rapid Synthesis of Nickel Hydroxide/Pt-Based Alloy Heterointerface for Hydrogen Evolution in Full pH Range.

The huge application potential of nanoelectrocatalysts can become available only under the condition of scalable and reproducible preparation of nanomaterials (NMs). It is easily overlooked that most of the preparation methods for efficient platinum (Pt)-based electrocatalysts are complicated in process and time-/energy-consuming, which is not conducive to scalable and sustainable production. Herein, we propose a rapid and facile method to in situ construct a heterointerface between nickel hydroxide (Ni(OH)2) and NiPt alloy, in which the preparation steps are easy-to-operate and can be finished in 1 h. Furthermore, the ensemble effect between the Ni(OH)2 substrate and NiPt active sites benefits the water dissociation process in nonacidic conditions, while the electronic effect in NiPt contributes to the downshifted d-band center of Pt and the proper Gibbs free energy of hydrogen species. As a result, the well-designed and quickly constructed Ni(OH)2-Ni3Pt heterointerfaces reveal lower overpotentials for HER compared with most reported Pt-based and commercial Pt/C catalysts in nonacidic conditions. This study is expected to provide useful reference information for the development of facile and robust methods for the preparation of more efficient Pt-based electrocatalysts.

Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

Deletion of Bmal1 in aggrecan-expressing cells leads to mouse temporomandibular joint osteoarthritis.

INTRODUCTION: Articular cartilage is the major affected tissue during the development of osteoarthritis (OA) in temporomandibular joint (TMJ). The core circadian rhythm molecule Bmal1 regulates chondrocyte proliferation, differentiation and apoptosis; however, its roles in condylar cartilage function and in TMJ OA have not been fully elucidated. MATERIALS AND METHODS: TMJ OA mouse model was induced by unilateral anterior crossbite (UAC) and Bmal1 protein expression in condylar cartilage were examined by western blot analysis. To determine the role of Bmal1 in TMJ OA, we generated cartilage-specific Bmal1 conditional knockout (cKO) mice (Bmal1Agc1CreER mice) and hematoxylin and eosin staining, toluidine blue and Safranin O/fast green, immunohistochemistry, TUNEL assay, real-time PCR analysis and Western blot assay were followed. RESULTS: Bmal1 expression was reduced in condylar cartilage in a TMJ OA mouse model induced by UAC. The Bmal1 cKO mice displayed decreased cartilage matrix synthesis, reduced chondrocyte proliferation, increased chondrocyte hypertrophy and apoptosis as well as the upregulation of YAP expression in TMJ condylar cartilage. CONCLUSIONS: We demonstrated that Bmal1 was essential for TMJ tissue homeostasis and loss-of-function of Bmal1 in chondrocytes leads to the development of TMJ OA.

Body shape from birth to adulthood is associated with skeletal development: A Mendelian randomization study.

BACKGROUND: Observational studies have shown that childhood obesity is associated with adult bone health but yield inconsistent results. We aimed to explore the potential causal association between body shape and skeletal development. METHODS: We used two-sample Mendelian randomization (MR) to estimate causal relationships between body shape from birth to adulthood and skeletal phenotypes, with exposures including placental weight, birth weight, childhood obesity, BMI, lean mass, fat mass, waist circumference, and hip circumference. Independent genetic instruments associated with the exposures at the genome-wide significance level (P < 5 × 10-8) were selected from corresponding large-scale genome-wide association studies. The inverse-variance weighted analysis was chosen as the primary method, and complementary MR analyses included the weighted median, MR-Egger, weighted mode, and simple mode. RESULTS: The MR analysis shows strong evidence that childhood (ß = -1.29 × 10-3, P = 8.61 × 10-5) and adulthood BMI (ß = -1.28 × 10-3, P = 1.45 × 10-10) were associated with humerus length. Tibiofemoral angle was negatively associated with childhood BMI (ß = -3.60 × 10-1, P = 3.00 × 10-5) and adolescent BMI (ß = -3.62 × 10-1, P = 2.68 × 10-3). In addition, genetically predicted levels of appendicular lean mass (ß = 1.16 × 10-3, P = 1.49 × 10-13), whole body fat mass (ß = 1.66 × 10-3, P = 1.35 × 10-9), waist circumference (ß = 1.72 × 10-3, P = 6.93 × 10-8) and hip circumference (ß =1.28 × 10-3, P = 4.34 × 10-6) were all associated with tibia length. However, we found no causal association between placental weight, birth weight and bone length/width. CONCLUSIONS: This large-scale MR analysis explores changes in growth patterns in the length/width of major bone sites, highlighting the important role of childhood body shape in bone development and providing insights into factors that may drive bone maturation.

Discovery of a novel homocysteine thiolactone hydrolase and the catalytic activity of its natural variants.

Homocysteine thiolactone (HTL), a toxic metabolite of homocysteine (Hcy) in hyperhomocysteinemia (HHcy), is known to modify protein structure and function, leading to protein damage through formation of N-Hcy-protein. HTL has been highly linked to HHcy-associated cardiovascular and neurodegenerative diseases. The protective role of HTL hydrolases against HTL-associated vascular toxicity and neurotoxicity have been reported. Although several endogeneous enzymes capable of hydrolyzing HTL have been identified, the primary enzyme responsible for its metabolism remains unclear. In this study, three human carboxylesterases were screened to explore new HTL hydrolase and human carboxylesterase 1 (hCES1) demonstrates the highest catalytic activity against HTL. Given the abundance of hCES1 in the liver and the clinical significance of its single-nucleotide polymorphisms (SNPs), six common hCES1 nonsynonymous coding SNP (nsSNPs) variants were examined and characterized for their kinetic parameters. Variants E220G and G143E displayed 7.3-fold and 13.2-fold lower catalytic activities than its wild-type counterpart. In addition, the detailed catalytic mechanism of hCES1 for HTL hydrolysis was computational investigated and elucidated by Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) method. The function of residues E220 and G143 in sustaining its hydrolytic activity of hCES1 was analyzed, and the calculated energy difference aligns well with experimental-derived results, supporting the validity of our computational insights. These findings provide insights into the potential protective role of hCES1 against HTL-associated toxicity, and warrant future studies on the possible association between specific genetic variants of hCES1 with impaired catalytic function and clinical susceptibility of HTL-associated cardiovascular and neurodegenerative diseases.

Propofol improves sleep deprivation-induced sleep structural and cognitive deficits via upregulating the BMAL1 expression and suppressing microglial M1 polarization.

BACKGROUND: Sleep deprivation (SD) is a growing global health problem with many deleterious effects, such as cognitive impairment. Microglia activation-induced neuroinflammation may be an essential factor in this. Propofol has been shown to clear sleep debt after SD in rats. This study aims to evaluate the effects of propofol-induced sleep on ameliorating sleep quality impairment and cognitive decline after 48 h SD. METHODS: Almost 8-12-week-old rats were placed in the SD system for 48 h of natural sleep or continuous SD. Afterwards, rats received propofol (20 mg·kg-1·h-1, 6 h) via the tail or slept naturally. The Morris water maze (MWM) and Y-maze test assessed spatial learning and memory abilities. Rat EEG/EMG monitored sleep. The expression of brain and muscle Arnt-like protein 1 (BMAL1), brain-derived neurotrophic factor (BDNF) in the hippocampus and BMAL1 in the hypothalamus were assessed by western blot. Enzyme-linked immunosorbent assay detected IL-6, IL-1ß, arginase 1 (Arg1), and IL-10 levels in the hippocampus. Immunofluorescence was used to determine microglia expression as well as morphological changes. RESULTS: Compared to the control group, the sleep-deprived rats showed poor cognitive performance on both the MWM test and the Y-maze test, accompanied by disturbances in sleep structure, including increased total sleep time, and increased time spent and delta power in non-rapid eye movement sleep. In addition, SD induces abnormal expression of the circadian rhythm protein BMAL1, activates microglia, and causes neuroinflammation and nerve damage. Propofol reversed these changes and saved sleep and cognitive impairment. Furthermore, propofol treatment significantly reduced hippocampal IL-1ß and IL-6 levels, increased BDNF, Arg1, and IL-10 levels, and switched microglia surface markers from the inflammatory M1 type to the anti-inflammatory M2 type. CONCLUSION: Propofol reduces SD-induced cognitive impairment and circadian rhythm disruption, possibly by lowering neuronal inflammation and switching the microglia phenotype from an M1 to an M2 activated state, thus exerting neuroprotective effects.