Unveiling Ionized Interfacial Water-Induced Localized H* Enrichment for Electrocatalytic Nitrate Reduction.

Electrocatalytic nitrate reduction reaction (NO3RR) is a process that requires the participation of eight electrons and nine protons. The regulation of active hydrogen (H*) supply and a deep understanding of related processes are necessary for improving the ammonia yield rate and Faradaic efficiency (FE). Herein, we synthesized a series of atomically precise copper-halide clusters Cu2X2(BINAP)2 (X = Cl, Br, I), among which the Cu2Cl2(BINAP)2 cluster shows the optimal ammonia FE of 94.0% and an ammonia yield rate of 373 µmol h-1 cm-2. In situ experiments and theoretical calculations reveal that halogen atoms, especially Cl in Cu2Cl2(BIANP)2, can significantly affect the distance of alkali metal-ionized water on the catalyst surface, which can promote the water dissociation to enhance the localized H* enrichment for the continues hydrogenation of nitrate to ammonia. This work explains the role of H* in the hydrogenation process of NO3RR and the importance of localized H* enrichment strategy for improving the FEs.

An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases.

T cells play a critical and irreplaceable role in maintaining overall health. However, their functions undergo alterations as individuals age. It is of utmost importance to comprehend the specific characteristics of T-cell aging, as this knowledge is crucial for gaining deeper insights into the pathogenesis of aging-related diseases and developing effective therapeutic strategies. In this review, we have thoroughly examined the existing studies on the characteristics of immune organ aging. Furthermore, we elucidated the changes and potential mechanisms that occur in T cells during the aging process. Additionally, we have discussed the latest research advancements pertaining to T-cell aging-related diseases. These findings provide a fresh perspective for the study of T cells in the context of aging.

Transformable 3D curved high-density liquid metal coils - an integrated unit for general soft actuation, sensing and communication.

Rigid solenoid coils have long been indispensable in modern intelligent devices. However, their sparse structure and challenging preparation of flexible coils for soft robots impose limitations. Here, a transformable 3D curved high-density liquid metal coil (HD-LMC) is introduced that surpasses the structural density level of enameled wire. The fabrication technique employed for high-density channels in elastomers is universally applicable. Such HD-LMCs demonstrated excellent performance in pressure, temperature, non-contact distance sensors, and near-field communication. Soft electromagnetic actuators thus achieved significantly improved the electromagnetic force and power density. Moreover, precise control of swinging tail motion enables a bionic pufferfish to swim. Finally, HD-LMC is further utilized to successfully implement a soft rotary robot with integrated sensing and actuation capabilities. This groundbreaking research provides a theoretical and experimental basis for expanding the applications of liquid metal-based multi-dimensional complex flexible electronics and is expected to be widely used in liquid metal-integrated robotic systems.

Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.

Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM.

Scalp Acupuncture Synchronizing Dual Task Gait for Enhancing Prefrontal Cortex Response.

Studies have shown that motor-cognitive dual task can greatly improve motor/cognitive function. However, the therapeutic effect of motor-cognitive dual task is still limited. How to improve dual-task performance is the key to solving this problem. Scalp acupuncture is a non-drug intervention method of traditional Chinese medicine to treat brain-derived diseases by acupuncturing the corresponding projection area of cerebral cortex function on the scalp. Studies have shown that scalp acupuncture helps improve neuronal damage and cognitive dysfunction and plays a neuroprotective function in central nervous system diseases. However, no relevant studies have discussed the synergistic gain effect of motor-cognitive dual task and scalp acupuncture. Therefore, this protocol aims to demonstrate the standardized operation of scalp acupuncture synchronizing motor-cognitive dual task and motor-cognitive dual task and compares the differences between these two tasks in healthy subjects through a randomized cross-over trial. This protocol initially revealed the possible influence mechanism of scalp acupuncture synchronizing motor-cognitive dual task on cognitive performance, gait control, and cortical brain function, which can provide new ideas and a theoretical basis for clinical exploration of new and effective non-drug treatment of integrated Chinese and Western medicine.

Generation of an induced pluripotent stem cell line from a Brugada syndrome patient carrying SCN5A/c.3118G>C mutation.

Brugada syndrome (BrS) is a hereditary arrhythmia syndrome characterized by right bundle branch block on an electrocardiogram and persistent ST-segment elevation in the right precordial leads. In this study, we describe the establishment of an induced pluripotent stem cell (iPSC) line derived from a BrS patient carrying the novel heterogeneous missense mutation (c.3118G>C; p.G1040R) in the sodium channel protein type 5 subunit alpha (SCN5A) gene. Skin fibroblasts underwent reprogramming using a non-integrated Sendai viral method. Generated iPSC line exhibited embryonic stem cell-like morphology, maintained a normal karyotype, expressed pluripotency markers, and demonstrated the capacity to differentiate into three germ layers.

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis.

Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1ß production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1ß production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Icariin protects against acute graft-versus-host disease while preserving graft-versus-leukemia activity after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE: This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS: Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS: Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION: These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.

Residual and bidirectional LSTM for epileptic seizure detection.

Electroencephalogram (EEG) plays a pivotal role in the detection and analysis of epileptic seizures, which affects over 70 million people in the world. Nonetheless, the visual interpretation of EEG signals for epilepsy detection is laborious and time-consuming. To tackle this open challenge, we introduce a straightforward yet efficient hybrid deep learning approach, named ResBiLSTM, for detecting epileptic seizures using EEG signals. Firstly, a one-dimensional residual neural network (ResNet) is tailored to adeptly extract the local spatial features of EEG signals. Subsequently, the acquired features are input into a bidirectional long short-term memory (BiLSTM) layer to model temporal dependencies. These output features are further processed through two fully connected layers to achieve the final epileptic seizure detection. The performance of ResBiLSTM is assessed on the epileptic seizure datasets provided by the University of Bonn and Temple University Hospital (TUH). The ResBiLSTM model achieves epileptic seizure detection accuracy rates of 98.88-100% in binary and ternary classifications on the Bonn dataset. Experimental outcomes for seizure recognition across seven epilepsy seizure types on the TUH seizure corpus (TUSZ) dataset indicate that the ResBiLSTM model attains a classification accuracy of 95.03% and a weighted F1 score of 95.03% with 10-fold cross-validation. These findings illustrate that ResBiLSTM outperforms several recent deep learning state-of-the-art approaches.

Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers.

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936-1.105 and 1.012-1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610-0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851-0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions.

Post-Operative Radiation in Early Breast Cancer with N1 Disease: 10-Year Follow-Up.

Post-operative radiotherapy for post-menopausal women with early breast cancer and N1 disease is controversial. Although locoregional control is improved, overall survival (OS) benefit is unclear. The clinical benefit of post-operative irradiation in this group of patients over 10 years was reviewed. We aimed to evaluate the OS, disease-free survival (DFS), and factors affecting OS and DFS. A retrospective review of 191 post-menopausal women with early breast cancer and N1 disease from 2004 to 2011 was performed. Demographics, post-operative histology, adjuvant treatment, OS, and DFS were evaluated. Post-operative radiation was given to 95 of 191 women (49.7%). Younger age at diagnosis (p < 0.001), a greater number of involved nodes (p = 0.004), lymphovascular invasion (LVI), and a higher tumor grade (p = 0.001) were more likely in women who received post-operative radiation. Nodal radiation did not improve 10-year DFS (p = 0.084) or OS (p = 0.203). Post-operative nodal radiation was associated with significant improvement in 10-year OS in women who received only hormonal therapy (p = 0.047) and no other systemic therapy. Women with unfavorable risk factors were more likely to receive post-operative radiation, likely due to a perceived higher risk of recurrence. Nodal radiation did not significantly improve 10-year DFS or OS in early breast cancer patients with N1 disease, and the benefit was not clearly demonstrated. However, in those who were on hormonal therapy, radiotherapy was beneficial in improving overall survival.

Identification of a novel HLA-C allele, HLA-C*02:246.

HLA-C*02 246 has one nucleotide change from HLA-C*02:02:02:01 at nucleotide 523 changing Arginine to Cysteine at residue 151.

Synthesis of Indole-Fused Pyrazino[1,2-a]quinazolinones by Copper(I)-Catalyzed Selective Hydroamination-Cyclization of Alkynyl-tethered Quinazolinones.

We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39 %-99 % under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.

Developing and validating a knowledge-based AI assessment system for learning clinical core medical knowledge in otolaryngology.

BACKGROUND: Clinical core medical knowledge (CCMK) learning is essential for medical trainees. Adaptive assessment systems can facilitate self-learning, but extracting experts' CCMK is challenging, especially using modern data-driven artificial intelligence (AI) approaches (e.g., deep learning). OBJECTIVES: This study aims to develop a multi-expert knowledge-aggregated adaptive assessment scheme (MEKAS) using knowledge-based AI approaches to facilitate the learning of CCMK in otolaryngology (CCMK-OTO) and validate its effectiveness through a one-month training program for CCMK-OTO education at a tertiary referral hospital. METHODS: The MEKAS utilized the repertory grid technique and case-based reasoning to aggregate experts' knowledge to construct a representative CCMK base, thereby enabling adaptive assessment for CCMK-OTO training. The effects of longitudinal training were compared between the experimental group (EG) and the control group (CG). Both groups received a normal training program (routine meeting, outpatient/operation room teaching, and classroom teaching), while EG received MEKAS for self-learning. The EG comprised 22 UPGY trainees (6 postgraduate [PGY] and 16 undergraduate [UGY] trainees) and 8 otolaryngology residents (ENT-R); the CG comprised 24 UPGY trainees (8 PGY and 16 UGY trainees). The training effectiveness was compared through pre- and post-test CCMK-OTO scores, and user experiences were evaluated using a technology acceptance model-based questionnaire. RESULTS: Both UPGY (z = -3.976, P < 0.001) and ENT-R (z = -2.038, P = 0.042) groups in EG exhibited significant improvements in their CCMK-OTO scores, while UPGY in CG did not (z = -1.204, P = 0.228). The UPGY group in EG also demonstrated a substantial improvement compared to the UPGY group in CG (z = -4.943, P < 0.001). The EG participants were highly satisfied with the MEKAS system concerning self-learning assistance, adaptive testing, perceived satisfaction, intention to use, perceived usefulness, perceived ease of use, and perceived enjoyment, rating it between an overall average of 3.8 and 4.1 out of 5.0 on all scales. CONCLUSIONS: The MEKAS system facilitates CCMK-OTO learning and provides an efficient knowledge aggregation scheme that can be applied to other medical subjects to efficiently build adaptive assessment systems for CCMK learning. Larger-scale validation across diverse institutions and settings is warranted further to assess MEKAS's scalability, generalizability, and long-term impact.

Experimental study of the biological properties of nmHA-SiO2 fiber materials prepared by electrospinning technology.

To study the biocompatibility of nanohydroxyapatite (nmHA)-SiO2 fiber material and its efficacy in guided bone regeneration. ① The cytotoxicity of the nmHA-SiO2 fiber material to MC3T3-E1 cells was determined by CCK-8 assay. The adhesion of cells on the surface of the material was observed. ② Bone defects were prepared in the skull of three groups of New Zealand white rabbits. The following treatments were administered: implantation of nmHA-SiO2, implantation of Bio-Oss, and no treatment. The defects were then covered with nmHA-SiO2 membrane or Hai'ao oral repair membrane. Animal samples were analyzed by gross observation, micro-computed tomography, hematoxylin-eosin staining and Masson staining. The data were statistically analyzed by multivariate analysis of variance to evaluate the repair of bone defects. ① The nmHA-SiO2 fiber material has suitable biocompatibility. ② The nmHA-SiO2 fiber material performed more effectively as a barrier membrane than other bone substitute materials in GBR model rabbits.

HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes.

HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known (ACY3, HAAO, HNF1A, MAP3K11) and previously unidentified (ABCD3, CDKN2AIP, USH1C, VIL1) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1, GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation.

Assessment of the exposure to cytotoxic Bacillus cereus group genotypes through HTST milk consumption.

This study addresses the limited tools available for assessing food safety risks from cytotoxic Bacillus cereus group strains in contaminated food. We quantified the growth, in skim milk broth, of 17 cytotoxic B. cereus strains across 6 phylogenetic groups with various virulence gene profiles. The strains did not grow in HTST milk at 4 or 6°C. At 10°C, 15 strains exhibited growth; at 8°C, one strain grew; and all strains grew at temperatures ≥ 14°C. Using growth data from 16 strains, we developed linear secondary growth models and an exposure assessment model. This model, simulating a 5-stage HTST milk supply chain and up to 35 d of consumer storage with an initial contamination of 100 cfu/mL, estimated that 2.81 ± 0.66% and 4.13 ± 2.53% of milk containers would surpass 105 cfu/mL of B. cereus by d 21 and 35, respectively. A sensitivity analysis identified the initial physiological state of cells (Q0) as the most influential variable affecting predictions for specific isolates. What-if scenarios indicated that increases in mean and variability of consumer storage temperatures significantly affected the predicted B. cereus concentrations in milk. This model serves as an initial tool for risk-based food safety decision making regarding low-level B. cereus contamination.

Photonic-assisted wideband microwave frequency measurement based on optical heterodyne detection.

A photonic-assisted microwave frequency measurement (MFM) method based on optical heterodyne detection is proposed and experimentally demonstrated. In the proposed MFM system, a linearly chirped optical waveform (LCOW) from a three-electrode distributed Bragg reflector laser diode (DBR-LD) and a multi-wavelength signal from a Mach-Zehnder modulator (MZM), where the signal under test (SUT) is modulated on an optical carrier from a distributed feedback laser diode (DFB-LD), are heterodyne detected by the photodetector (PD). A bandpass filter then filters the detected signal, and the envelope is detected by an oscilloscope. Then, frequency-to-time mapping is realized, and the signal frequency is measured. Thanks to the fast tuning rate and large tuning range of the DBR-LD, the proposed MFM system has a high measurement speed and a broad instantaneous measurement bandwidth. In the experimental demonstration, a measurement error below 39.1 MHz is achieved at an instantaneous bandwidth of 20 GHz and a measurement speed of 1.12 GHz/µs. The MFM of a frequency-hopping signal is also experimentally demonstrated. The successful demonstration of the MFM system with a simple structure provides a new optical solution for realizing broadband and fast microwave frequency measurements.

Prevention and control of venous thromboembolism after major orthopedic surgery through doctor-to-patient cultivation of musculoskeletal ability based on King's theory of goal attainment.

OBJECTIVES: To explore the prevention and management of venous thromboembolism (VTE) following major orthopaedic surgery (MOS) by fostering doctor-to-patient cultivation of musculoskeletal ability, guided by King's theory of goal attainment. METHODS: A cohort of patients (n = 116) undergoing MOS was selected for the study, and were divided into two groups: the regular group and the observation group, with patients in the regular group experiencing routine nursing care and management and those in the observation group undergoing musculoskeletal ability cultivation based on King's theory of goal attainment. Baseline data, limb vascular ultrasonography, coagulation function, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, VTE prevention efficacy, Exercise of Self-care Ability Scale (ESCA) score, and nursing satisfaction were analysed comparatively. RESULTS: There was no significant within-group difference in baseline data (P > 0.05). Following the interventions, the observation group demonstrated statistically significant reductions in the Musculoskeletal-Integrated Imaging Score, various dimensions of WOMAC scores, and D-dimer (D-D) levels (P < 0.05) both in comparison to their levels before interventions and to those observed in the regular group (P < 0.05). Additionally, the observation group exhibited increases in prothrombin time levels and various dimensions of ESCA scores (P < 0.05) post-intervention, surpassing the pre-intervention levels and those obtained in the regular group (P < 0.05). Furthermore, the observation group exhibited a significantly lower incidence of VTE (P < 0.05) and higher nursing satisfaction (P < 0.05) compared to the regular group. CONCLUSIONS: Nursing intervention measures, utilizing doctor-to-patient cultivation of musculoskeletal ability based on King's theory of goal attainment, have demonstrated a significant clinical benefit for VTE prevention and control in post-MOS patients. This approach not only effectively prevented VTE in post MOS patients but also enhanced their satisfaction towards nursing care.