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A series of novel β-carbolines with a flexible amino side chain at positions 1 and 3, respectively, were designed, synthesized and evaluated as potential antitumor agents. The results revealed that most of the compounds exhibited a broad spectrum of antiproliferative activity with IC 50 value lower than 20 μM against human tumor cell lines. Among them, compound 2f was the most potent antiproliferative agent with IC 50 value below 5.0 μM against human tumor cell lines. Subsequent studies on the in vivo antitumor efficacy of the representative compound 2f demonstrated its ability to hinder tumor progression and significantly diminish tumor mass in a mouse model of colorectal cancer. Further investigation on mechanisms of action showed that compound 2f induced autophagy via the ATG5/ATG7 pathway in HCT116 cells. These compounds may contribute to the development of therapeutic agents for colorectal cancer., Competing Interests: Declaration of competing interest All authors have read and approved this version of the article, and due care has been taken to ensure the integrity of the work. No part of this paper has been published or submitted elsewhere. No conflict of interest exists in the submission of this manuscript., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: One of the etiologic components of degenerative spinal illnesses is intervertebral disc degeneration (IVDD), and the accompanying lower back pain is progressively turning into a significant public health problem. Important pathologic characteristics of IVDD include inflammation and acidic microenvironment, albeit it is unclear how these factors contribute to the disease., Purpose: To clarify the functions of inflammation and the acidic environment in IVDD, identify the critical connections facilitating glycolytic crosstalk and nucleus pulposus cells (NPCs) pyroptosis, and offer novel approaches to IVDD prevention and therapy., Methods: By developing keywords search strategy, literature was found and screened using databases such as PUBMED, Google Scholar, Web of Science, China National Knowledge Infrastructure, and others. Hub genes, protein interaction networks, clinical transcriptome data validation, and enrichment analysis were used to further validate relevant biological pathways., Results: It is clear that disc degeneration is associated with apoptosis or pyroptosis, inflammation, and an acidic environment based on literature review. The process of IVDD is intimately associated with pyroptosis, inflammation, and an acidic environment. The precise mechanism may entail the regulation of key genes such NLRP3, ASIC1a, IL1β, TNF-a, and GSDMD. While the acidic environment exacerbated extracellular matrix degradation and promoted cellular senescence and inflammatory factor expression, it was found to be unfavorable for NPCs survival and proliferation. Moreover, NPCs pyroptosis in an acidic environment, the molecular mechanism behind this phenomenon may be connected to ASIC1a mediated Ca + influx. On the other hand, IVDD can be constantly promoted by the interaction between the degenerating disc's acidic and inflammatory environments through "crosstalk" between anaerobic glycolysis and positive feedback., Conclusion: In summary, the inflammatory process in NPCs is made worse by the buildup of glucose brought on by metabolic problems, such as anaerobic glycolytic processes, and pyroptosis caused by excessive glucose may be mitigated by inhibiting endoplasmic reticulum stress. A new therapeutic approach for IVDD will involve using ASIC1a as a regulatory target to enhance the inflammatory environment and decrease the incidence of NPCs pyroptosis. Following this, anaerobic glycolysis will be regulated, lactic acid generation will be reduced, and the degenerative vicious loop will be blocked., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The molecular of intervertebral disc degeneration (IVDD) is still unclear. When it comes to treating decoction, traditional Chinese medicine is effective. In particular, the Duhuo (Radix Angelicae Biseratae) may be particularly helpful., Purpose: To identify nucleus pulposus cells (NPCs) subpopulations and immune cells and clarify the mechanism of IVDD therapy, offering recommendations for diagnosis and treatment., Methods: IVDD targets from the Genecards and microarray data from biological databases. To find the key genes and biological pathways underlying IVDD, multiple machine learning techniques were used. IVDD is associated with subpopulations of NPCs as revealed by single-cell analysis, and immunological infiltration was identified by Immune Cell AI. To validate the molecular pathways by which Duhuo activity affects IVDD, network pharmacology and molecular docking were employed., Results: The process of IVDD is linked to key genes like TP53, JUN, PTEN, IL1B, ERBB2, MAPK8, CASP9, PTK2, etc. The main molecular mechanisms involved in this process are immune responses, inflammatory factors expression, cellular responses to mechanical stimuli, and NPC apoptosis. Immune Cell AI discovered a correlation between CD4 naïve, B cell, monocyte, NK, and macrophage infiltration with the development of IVDD. The NPC subtypes associated with IVDD, namely fibroNPCs, adhesion NPCs, regulatory NPCs, homeostatic NPCs, and hypertrophic chondrocyte-like NPCs (HT-CL NPCs), were the subject of single-cell mapping. We also found that Osthole, Columbianadin, and Bergapten, the principal blood entry components of Dohuo, may have a role by modulating CASP9, MAPK8, PTGS1, and PARP1, the targets of apoptosis., Conclusion: The NPC subpopulations that exist in IVDD are HT-CL NPCs, fibroNPCs, adhesion NPCs, regulatory NPCs, and homeostatic NPCs. Furthermore, a variety of immune cell infiltrates, particularly monocyte and macrophage, have a significant impact on the advancement of IVDD. Osthole, Columbianadin, and Bergapten, the principal components of Duhuo, absorb IVDD via controlling the death of NPCs., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Food-Drug Interaction (FDI) refers to the phenomenon where food affects the pharmacokinetic or pharmacodynamic characteristics of a drug, significantly altering the drug's absorption rate or absorption extent. These Interactions are considered as a primary determinant in influencing the bioavailability of orally administered drugs within the gastrointestinal tract. The impact of food on drug absorption is complex and multifaceted, potentially involving alterations in gastrointestinal physiology, increases in splanchnic blood flow rates, and shifts in the gut microbiota's composition. Up to now, extensive research has focused on the interactions between food composition (such as proteins, fats, and vitamins) and drug absorption. In contrast, the impact of food physical properties (such as viscosity, volume, and pH) has received less attention in drug development. This article reviewed the impact of food properties on oral drug absorption based on a comprehensive literature search, focusing on the influence of food volume and food viscosity. From the perspective of pharmacokinetics, we examined interaction trends between food properties and drugs across different classification based on the Biopharmaceutics Classification System (BCS). In addition, we introduced the practical application of physiologically based pharmacokinetic (PBPK) modeling in predicting oral drug absorption under the influence of food Properties., Competing Interests: The authors report no conflicts of interest in this work., (© 2025 Wang et al.)

Background: Postmenopausal Osteoporosis (PMOP) is characterized by decreased bone mass and deterioration of bone microarchitecture, leading to increased fracture risk. Current treatments often have adverse effects, necessitating safer alternatives. Kaempferol, a flavonoid identified as a key active component of the traditional Chinese medicine Yishen Gushu formula, has shown promise in improving bone health, but its mechanisms in PMOP treatment remain unclear., Objective: The aim of this study was to investigate the therapeutic effects and underlying mechanisms of kaempferol in the treatment of PMOP., Methods: A bilateral ovariectomized (OVX) rat model was established to simulate PMOP. Sixty female Sprague-Dawley rats were divided into six groups: Sham operation, OVX control, OVX with alendronate (ALN), and OVX with kaempferol at doses of 10, 20, and 40 mg/kg. Treatments were administered orally once daily for 12 weeks. Assessments included Bone Mineral Density (BMD), trabecular microarchitecture via histopathology, organ morphology, organ indices, and serum levels of bone metabolism markers (TRACP-5b, BALP, ALP, Ca, P, and Fe) as well as liver and kidney function indicators (ALT, AST, CREA, and urea). Tandem Mass Tag (TMT) quantitative proteomics and bioinformatics analyses were conducted on femur samples to identify differentially expressed proteins (DEPs). Key DEPs were validated using parallel reaction monitoring (PRM), immunohistochemistry, and molecular docking., Results: Kaempferol significantly improved BMD and enhanced trabecular microarchitecture in OVX rats in a dose-dependent manner, comparable to ALN, without causing hepatic, renal, or estrogen- like side effects. Serum bone metabolism markers were normalized with kaempferol treatment. Proteomic analysis identified 902 DEPs associated with kaempferol treatment, involved in processes such as bone remodeling, skeletal system development, and osteoclast function. Key signaling pathways affected included NF-κB, PI3K-AKT, and HIF-1. Notably, kaempferol downregulated five key DEPs-Rac2, Ddb1, Cdc42, Rpl19, and Hist2h4-in the femur, which are crucial for osteoclast resorptive activity, migration, adhesion, and cell cycle progression., Conclusion: Kaempferol exerts therapeutic effects on PMOP by inhibiting key proteins involved in osteoclast function, thereby reducing bone resorption and promoting bone health. These findings suggested that kaempferol is a potential safer alternative for PMOP treatment. Further research is recommended to explore its clinical applications and elucidate detailed mechanisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The treatment of antibiotic wastewater often faces the challenge of simultaneously and effectively degrading multiple components under complex conditions. To address this challenge, magnetite nanoparticles doped ultrafine activated charcoal powder (MNPs/UACP), which effectively catalyzed the decomposition of H 2 O 2 into •OH and HO 2 •, was prepared using chemical co-precipitation. Under optimum conditions (i.e., tetracycline (TC) concentration = 100 ppm, pH = 3, H 2 O 2 concentration = 4.9 mM, catalyst dosage = 0.5 g/L), the 50% MNPs/UACP-H 2 O 2 system achieved 97.5% TC removal within 180 min, driven by the synergistic action between adsorption and catalytic oxidation. The stability of 50% MNPs/UACP in recycling was evaluated through repeated reaction cycles, demonstrating that the TC removal efficiency remained at 91.0% even after five cycles. The competition among TC, oxytetracycline (OTC), and chloramphenicol (CAP) in the MNPs/UACP-H 2 O 2 system was closely related to the catalytic oxidation performance, and increasing the proportion of MNPs in MNPs/UACP to above 50% effectively reduced the competition, optimizing degradation efficiency. This study is among the first to provide a comprehensive understanding of adsorption-catalytic oxidation coupled system, offering new insights for broad environmental applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

A limited number of cohort studies have explored the impact of serum essential metal elements on blood pressure (BP) or glycolipids and their regulatory mechanism in children. This study aimed to investigate the relationship between serum metal concentrations of iron (Fe), zinc (Zn), calcium (Ca), copper (Cu), and magnesium (Mg) and BP in children, and explore the potential mediating effects of glycolipid profiles. This cohort study included 1993 children (3566 BP measurements) aged 6-14 years in Chongqing, China. Serum essential metals, BP, lipid profiles, and glucose and insulin levels were measured. The relationship between serum metal levels and BP was analyzed using generalized linear and regression models, and a mediation analysis was performed to examine the potential mediating role of glycolipids. After adjusting for confounders, positive associations were found between serum Fe and Zn levels and BP parameters (all P < 0.05). A "U" style relationship between Cu and BP was found. Stronger associations were found in children aged ≤ 10 years, with sex-specific differences for Fe, Zn, and Cu. The relationship between elevated BP and serum Mg and Ca was not found. Our study found that triglycerides showed a significant relationship with Fe and Zn levels (P < 0.005). Moreover, triglycerides, partially mediate the effects of Zn on elevated BP. Serum Fe, Zn, and Cu concentrations were associated with BP in children, and age and sex differences were observed. Triglycerides may play a mediating role. These findings highlight the importance of maintaining an optimal serum essential metal status for cardiovascular health in children and suggest potential early prevention strategies., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Local anesthetics (LAs: articaine, lidocaine, bupivacaine, and mepivacaine) are essential for dental pain management. However, there are concerns that the lipophilic LAs could cross into breast milk causing toxicity to the infant. Our objective was to establish a multi-analyte LC-MS/MS method for the concurrent quantification of local anesthetics (LAs) in human plasma and breast milk, clarifying the transfer of LAs from plasma to breast milk, thereby offering crucial data for the safe assessment of LAs during the nursing period. Sample preparation for plasma and breast milk involved protein precipitation and a single dilution step. The chromatographic analysis was conducted using an ACQUITY UPLC BEH C18 column. Detection was facilitated by a triple quadrupole mass spectrometer employing positive electrospray ionization. The method demonstrated excellent linearity for articaine, mepivacaine, and bupivacaine across the range of 0.5 to 500 ng/mL, and for lidocaine from 1.0 to 1000 ng/mL in both plasma and breast milk, with correlation coefficients (R2) of 0.99 or higher. The method was effectively utilized in the analysis of samples from three nursing mothers who received dental treatment involving LAs. Articaine and lidocaine excretion in milk was confirmed, but it presented no significant safety risks to the breastfed infants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolic-associated fatty liver disease (MAFLD) is an important public health problem, and the gut microbiota has become a new treatment target for MAFLD. Previously, A. indistinctus, a core gut bacterium, was shown to potentially contribute to the prevention of MAFLD. However, the effect and mechanism of A. indistinctus on MAFLD are still unclear and need to be investigated. This study primarily evaluated whether A. indistinctus can improve gut microbiota disorders and prevent the progression from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) in mice fed a high-fat diet (HFD). First, we observed that A. indistinctus significantly improved lipid metabolism disorders and reduced hepatic inflammation induced by HFD consumption in mice. We found that A. indistinctus improved gut barrier function and inhibited the LPS/TLR4/NF-κB pathway, thereby reducing hepatic inflammation. Moreover, 16S rRNA V3-V4 analyses revealed that A. indistinctus could significantly change the structure of the gut microbiota and increase the abundance of L. johnsonii by promoting its growth. Finally, we showed that L. johnsonii administration significantly improved lipid metabolism disorders and reduced hepatic lipid accumulation induced by HFD consumption in mice. In summary, A. indistinctus administration significantly reduces hepatic inflammation by improving gut barrier function and improves lipid metabolism disorders by promoting the growth of L. johnsonii. Our research improves the understanding of the gut microbiota and provides a basis for future therapeutic use of A. indistinctus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Precious metal electrical contact materials are pivotal in microelectronic devices due to their excellent chemical stability and electrical properties. Their practical application is hindered by the strength, contact resistance, and high cost. Multi-principal elements alloys (MPEAs) provide the possibility to develop cost-effective materials with enhanced mechanical properties. To address this, a novel precious metal MPEA, PdAgCuAuPtZn alloy, is designed, which exhibits significant solid solution strengthening and aging strengthening effects. The ultimate tensile strength increases from 747 MPa in the solution state to 1126 MPa in the aged state, while resistivity remains low. This study presents the first systematic investigation into the strengthening mechanisms of precious metal MPEAs using nanoindentation technology. These findings indicate that the aging strengthening of the alloy is attributed to spinodal decomposition (SD) and chemical short-range order (CSRO) in the matrix. Furthermore, the precipitation structure with Cu-rich and Ag-rich phases gradually replaces the matrix, primarily accounting for aging softening. Additionally, it is discovered that precipitation structure can be strengthened by CSRO formed in the Cu-rich phase, thus providing an innovative strengthening in PdAgCuAuPtZn alloy. These results will be beneficial to both deeply understanding the aging behaviors of PdAgCuAuPtZn alloys and designing high-performance precious metal MPEAs., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Bacterial contamination in platelets has been a major concern over the years. In this study, we showed that treatment with 420 nm visible light with various concentrations of riboflavin in platelets reduced E. coli and S. aureus by 0-1.56 and 0.3-2.02 logs (50 mW/cm 2 ), 2.24-4.77 and 0.73-3.26 logs (75 mW/cm 2 ), and ≥ 5.14 and ≥ 5.27 logs (100 mW/cm 2 ). Treatment with high-intensity light (100 mW/cm 2 ) and high concentrations of riboflavin (400 µM and 500 µM) effectively reduced both bacteria in platelets by over 4 logs. The study also found a positive correlation between bacterial reduction and light intensity, as well as riboflavin concentration in a dose-dependent manner. These results demonstrate the potential of using riboflavin and visible light to reduce the risk of bacterial contamination in platelets, and support the need for further exploration of pathogen reduction using 420 nm visible light and riboflavin., Competing Interests: Declaration of Competing Interest All authors declare that there are no potential competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Oligonucleotide drugs are anticipated to mark the new wave of pharmaceutical innovation, succeeding the eras of small molecule drugs and monoclonal antibodies. This review assessed a decade of global and Chinese clinical advancements in this field. Since 2013, there has been a notable surge in the development of oligonucleotide drugs, although a considerable majority of these candidates are still in the nascent stages of clinical trials. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) represent two pivotal classes both on global scale and within China. Rare diseases have been the main therapeutic target for oligonucleotide drugs, with a less pronounced focus in China's pipeline relative to the global trend. Concurrently, these drugs are broadening their scope to encompass a variety of indications, potentially revolutionizing treatment approaches for chronic conditions. While China's clinical development in this sector is in its infancy compared to the global stage, technological progress and favorable policies are expected to foster a new landscape of oligonucleotide drug development in the future., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Spatial distribution orientations of blocks can cause significant errors in the discrete element model (DEM) calculation of soil-rock mixture (SRM). To avoid this error, spherical harmonic (SH) series whose harmonization degrees fixed at 15 were proposed for block reconstruction. This research refers to the case-history of a deep excavation rift valley spanning from the Mabian to Zhaojue section of the Leshan-Xichang Expressway, mainly containing moderately-weathered silty mudstone, in the Leshan City, Sichuan Province, China. The appropriate degree of finite-term SH series is selected by the volume, surface area. 100 blocks were scanned on site, and sphericity and angularity of the blocks were calculated. The sphericity and angularity of 50 reconstructed blocks were considered for the error analysis of SH method. Moreover, stochastic polyhedron method was considered for comparing different block reconstructions. The maximum block placement angle was defined to control the spatial distribution orientations of the blocks. Large scale direct tests were carried. Numerical simulations of large-scale direct shear tests were conducted to study the influence of the spatial distribution orientations of the blocks on the mechanical properties of the SRMs. The results revealed that the finite-term SH series fixed at 15 accurately reflected the shape characteristics and mechanical behaviors of actual blocks. The spatial distribution orientations of the blocks had a minimal impact on the friction angle and cohesion of SRM constructed through the SH method. The SRMs developed via the SH method exhibited marginal variations in contact force and anisotropy index of contact across diverse block placement strategies. The evolution of coordination number was closer when employing the SH method under varied block placement methods. Blocks reconstructed by the SH method, could mitigate errors in DEM calculation caused by the spatial distribution orientations of the blocks., (© 2024. The Author(s).)

Previous research has shown that creative cognitive reappraisal is highly effective in regulating negative emotions. We conducted three experiments to explore its transferability. In Experiment 1, we observed that free recall performance was better for creative reappraisal compared to non-creative reappraisal. Memory retention of reappraisals was associated with creativity ratings, but not with perceived effectiveness ratings. In Experiment 2, participants generated reappraisals for newly introduced unpleasant images before (pre-session) and after (post-session) exposure to creative reappraisal, non-creative reappraisal, and descriptive control interpretation. Results showed increased reflective effectiveness of self-generated reappraisals in the post-session. The level of creativity of the self-generated reappraisals was associated with differences in perceived effectiveness between creative and non-creative exposed reappraisals. In Experiment 3, we investigated how two processing approaches (effectiveness-oriented vs. memory-oriented) influenced the transferability of creative reappraisal. We observed creativity levels of self-generated reappraisals increased in both conditions. The reflective effectiveness of the self-generated reappraisals tended to increase only in the effectiveness-oriented processing condition. Our findings demonstrate that recognising the effectiveness of creative reappraisal plays a crucial role in its transfer across different situations.

Background: Depression seriously affects the quality of life of breast cancer patients and even hinders treatment and recovery after diagnosis. Subthreshold depression should be worthy of attention, and the risk of subthreshold depression developing into depression increases if timely intervention is not available. However, there is limited research on interventions for subthreshold depression, especially for newly diagnosed breast cancer patients., Objective: Exploring the efficacy of a PERMA-based positive psychological intervention programme in newly diagnosed breast cancer patients with subthreshold depression., Methods: Using PERMA as a framework, we constructed the intervention programme through a literature review and expert discussion approach, and revised the programme using the Delphi method. Then we selected 84 newly diagnosed breast cancer patients for a randomised controlled trial. The control group received conventional care (primary care, specialist care, psychological care, etc.), and the observation group received a PERMA-based positive psychological intervention programme. Patient data were collected before and after the intervention, and the dataset consisted of patient responses to general information, the Depression Screening Scale (CES-D), the Hamilton Depression Inventory (HAMD-17), and the Questionnaire on Psychosocial Adjustment in Breast Cancer Patients., Results: A total of 79 patients completed the study (38 patients in the observation group and 41 patients in the control group), and before the intervention, there were no statistical differences in the comparison of general information, subthreshold depression scores, and psychosocial adaptation scores between the two groups ( p > 0.05). After the intervention, the subthreshold depression (CES-D and HAMD-17 scores) scores of the observation group were lower than those of the control group ( p  < 0.01), and the psychosocial adaptation scores were significantly higher than those of the control group ( p  < 0.01)., Conclusion: A positive psychological intervention programme using PERMA as a framework was more effective in reducing subthreshold depression levels and promoting levels of psychosocial adjustment in newly diagnosed breast cancer patients., Implications for Practice: Interventions for subthreshold depression are not limited to the traditional aftercare model, but rather from a positive psychology perspective. Especially for patients newly diagnosed with breast cancer, this is a new endeavour that has important implications for them. Because, instead of focusing on their negative emotions, we help them gradually adapt to their new identity and treatment process from a positive aspect during their most difficult period, thus reducing their subthreshold depression level and preventing it from developing into a more severe depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Li, Xin, Wu and Xia.)

Objectives: Few studies illustrate the mechanism between air temperature and blood pressure (BP) in childhood. This study aims to investigate the associations between air temperature, humidity exposure, and BP trajectories in children and adolescents, and explore the potential mediating roles of lipid profiles in these relationships., Methods: This prospective cohort study included 5,971 children with 10,800 person-times measurements at baseline from the Chongqing Health Cohort, with evaluations conducted in 2014-2015 (baseline) and follow-ups in 2016 (urban areas) and 2019 (urban and rural areas). Multilevel mixed-effects models were used to analyse the impacts of air temperature and humidity on BP levels and the incidence of elevated BP, while accounting for potential confounders. Mediation analyses were performed to evaluate the mediating effects of lipid profiles, including low-density lipoprotein (LDL), total cholesterol (TC), and specific lipid species., Results: After adjusting for covariates, higher air temperature quartiles were associated with both decreased BP levels and elevated BP risk (RR: 0.83; 95 % CIs: 0.78, 0.89; P = 0.028). Conversely, higher humidity quartiles exhibited a U-shaped relationship with BP levels. Greater variability in air temperature was linked to increase BP levels. The cumulative effects of air temperature exposure on BP were significant from pregnancy to age 10, with females exhibiting larger effects (β:-3.291, 95 % CIs: -4.242,-2.340, P < 0.001). LDL and TC partially mediated the associations between air temperature and BP levels, particularly in males. Specific lipid species, including SM (d21:1), LPC (17:0), and PC (O-36:3), also exhibited significant mediating effects., Conclusions: This study provides novel insights into the intricate interplay between air temperature, humidity, lipid metabolism, and blood pressure regulation in children. Lower average temperatures and extreme humidity levels were associated with increased risks of elevated BP, potentially mediated by lipid profiles. Early interventions targeting air temperature exposure and lipid metabolism could mitigate hypertension risk, promoting improved cardiovascular outcomes in children., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Antibody-drug conjugates (ADCs) have become a pivotal area in the research and development of antitumor drugs. They provide innovative possibilities for tumor therapy by integrating the tumor-targeting capabilities of monoclonal antibodies with the cytotoxic effect of small molecule drugs. Pharmacometrics, an important discipline, facilitates comprehensive understanding of the pharmacokinetic characteristics of ADCs by integrating clinical trial data through modeling and simulation. However, due to the complex structure of ADCs, their modeling approaches are still unclear. In this review, we analyzed published population pharmacokinetic models for ADCs and classified them into single-analyte, two-analyte, and three-analyte models. We also described the benefits, limitations, and recommendations for each model. Furthermore, we suggested that the development of population pharmacokinetic models for ADCs should be rigorously considered and established based on four key aspects: (1) research objectives; (2) available in vitro and animal data; (3) accessible clinical information; and (4) the capability of bioanalytical methods. This review offered insights to guide the application of pharmacometrics in the clinical research of ADCs, thereby contributing to more effective therapeutic development., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In recent years, virtual drug study, as an emerging research strategy, has become increasingly important in guiding and promoting new drug research and development. Researchers can integrate a variety of technical methods to improve the efficiency of all phases of new drug research and development, including the use of artificial intelligence, modeling and simulation for target identification, compound screening and pharmacokinetic characteristics evaluation, and the application of clinical trial simulation to carry out clinical research. This paper aims to elaborate on the application of virtual drug study in the key stages of new drug research and development and discuss the opportunities and challenges it faces in supporting new drug research and development., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects., Materials and Methods: In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up., Results: The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs., Conclusion: In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Hypertrophy ligamentum flavum is a prevalent chronic spinal condition that affects middle-aged and older adults. However, the molecular pathways behind this disease are not well comprehended., Objective: The objective of this work is to implement bioinformatics techniques in order to identify crucial biological markers and immune infiltration that are linked to hypertrophy ligamentum flavum. Further, the study aims to experimentally confirm the molecular mechanisms that underlie the hypertrophy ligamentum flavum., Methods: The corresponding gene expression profiles (GSE113212) were selected from a comprehensive gene expression database. The gene dataset for hypertrophy ligamentum flavum was acquired from GeneCards. A network of interactions between proteins was created, and an analysis of functional enrichment was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. An study of hub genes was performed to evaluate the infiltration of immune cells in patient samples compared to tissues from the control group. Finally, samples of the ligamentum flavum were taken with the purpose of validating the expression of important genes in a clinical setting., Results: Overall, 27 hub genes that were differently expressed were found through molecular biology. The hub genes were found to be enriched in immune response, chemokine-mediated signaling pathways, inflammation, ossification, and fibrosis processes, as demonstrated by GO and KEGG studies. The main signaling pathways involved include the TNF signaling pathway, cytokine-cytokine receptor interaction, and TGF-β signaling pathway. An examination of immunocell infiltration showed notable disparities in B cells (naïve and memory) and activated T cells (CD4 memory) between patients with hypertrophic ligamentum flavum and the control group of healthy individuals. The in vitro validation revealed markedly elevated levels of ossification and fibrosis-related components in the hypertrophy ligamentum flavum group, as compared to the normal group., Conclusion: The TGF-β signaling pathway, TNF signaling pathway, and related hub genes play crucial roles in the progression of ligamentum flavum hypertrophic. Our study may guide future research on fibrosis of the ligamentum flavum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Author(s). JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Evidences shows that T helper 17 (Th17) and regulatory T (Treg) cells imbalance plays a critical role in bone lesions of MM patients. Therefore, regulating the Th17/Treg imbalance may be beneficial for bone lesions in MM. Ten MM mice complicated with bone lesions were established and divided into the halofuginone (HF) group and the PBS group. After treatment, tibia and fibula from both groups were scanned by micro-CT. Osteoclasts and osteoblasts were validated by histochemical staining and ELISA. Th17 and Treg cells were tested by flow cytometry. The correlations between Th17/Treg cell ratio and osteoclasts, osteoblasts and bone remodeling were analyzed using the Spearman relative analysis. After treatment, mice in the HF group had an increase in trabecular bone volume fraction and thickened cortex, but a decrease in trabecular separation compared to mice in the PBS group.Tartrate-resistant acid phosphase (TRAP) + osteoclasts and its biomarker TRACP5b in serum were reduced, while alkaline phosphatase (ALP) + osteoblasts and its biomarker N-terminal propeptide of type 1precollagen (P1NP) in serum were accreted in the HF group. Th17/Treg cell ratio in halofuginone-treated mice was 0.85 ± 0.05, and was significantly lower than that in PBS-treated mice, which was 1.51 ± 0.03. In addition, it showed that the Th17/Treg cell ratio was significantly and positively associated with osteoclasts, but was significantly and negatively associated with osteoblasts and bone remodeling. Halofuginone plays a critical role in the amelioration bone lesions in MM, as it can inhibit osteoclastogenesis and enhance osteoblastogenesis by regulating the Th17/Treg cell balance., Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-024-01756-4., (© The Author(s) 2024.)

Aims: To document the prevalence of skin problems associated with insulin pump use and identify contributing factors among children with type 1 diabetes mellitus in China., Methods: In total, 461 children were recruited from an online community (i.e., a Wechat group) of pediatric patients with T1DM. A self-developed questionnaire was filled in by parents, collecting the information on social demographics, disease, and insulin pump therapy related characteristics and skin problems. We applied the Mann-Whitney U test, Chi square test and logistic regression analysis to identify the factors associated with skin problems., Results: Of the 461 responders, 308 (66.8 %) children were reported to have skin problems. More specifically, 38.8 % had pigmentation changes, 22.3 % allergy/dermatitis, 20.2 % scaring, 11.5 % pain, 10.8 % infection, 10.6 % subcutaneous lipohypertrophy, and 6.1 % lipoatrophy. Logistic regression analysis showed that independent associated factors of skin problems were the caregiver's educational level as college or above, patient having skin allergies, and using the Brand 2 insulin pump (p values < 0.05)., Conclusions: The present study documents the prevalence of skin problems and identifies associated factors, such as caregiver's education, patients skin allergies, and using a specific brand of pump. Health education should address these factors in addition to the traditionally emphasized factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Motion retargeting for animation characters has potential applications in fields such as animation production and virtual reality. However, current methods either assume that the source and target characters have the same skeletal structure, or require designing and training specific model architectures for each structure. In this paper, we aim to address the challenge of motion retargeting across previously unseen skeletal structures with a unified dynamic graph network. The proposed approach utilizes a dynamic graph transformation module to dynamically transfer latent motion features to different structures. We also take into consideration for intricate hand movements and model both torso and hand joints as graphs in a unified manner for whole-body motion retargeting. Our model allows the use of motion data from different structures to train a unified model and learns cross-structural motion retargeting in an unsupervised manner with unpaired data. Experimental results demonstrate the superiority of the proposed method in terms of data efficiency and performance on both seen and unseen structures.

Although reducing students' aggressive behaviors and improving their creativity are both important commitments of educators, they are usually treated independently as unrelated tasks. However, cumulative evidence suggests potential links between aggression and creativity, not only from the perspectives of personality traits and psychological development, but also from their shared cognitive mechanisms. This implies that there may be an approach to achieving these two goals through a single intervention. Moreover, this new approach may overcome the limitation of the usually adopted aggression intervention, which is limited in its regulatory effectiveness and might bring about some disadvantageous impacts on creativity that are closely associated with aggression. To test this possibility, the present study implemented a four-session, 2-week creative thinking training (CTT) intervention for students with high aggression scores to examine whether it could simultaneously downregulate aggression and increase creativity. Our results demonstrate that, compared to the control group, the intervention group experienced significant improvements in creativity and a reduction in aggression following the CTT intervention. Furthermore, our findings suggest that this regulatory effect can persist for up to 6 months. The CTT-induced creativity change (increase) could significantly correlate with and predict the CTT-induced aggression decrease, thus suggesting that the CTT could transform aggression into creativity., (© 2023 The Authors. PsyCh Journal published by Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

Background: To investigate the correlation between albumin-corrected anion gap(ACAG) within the first 24 hours of admission and in-hospital mortality in trauma patients in intensive care unit(ICU)., Materials and Methods: We utilized the MIMIC-Ⅲ and MIMIC-Ⅳ databases to examine trauma patients admitted to the ICU. The relationship between ACAG and in-hospital mortality in trauma patients was analyzed using Receiver Operating Characteristic(ROC) curve, Kaplan-Meier (K-M) survival curve, and Cox regression model. Propensity score matching (PSM) and subgroup analysis were conducted to enhance stability and reliability of the findings. Mortality at 30-day and 90-day served as secondary outcomes., Results: The study enrolled a total of 1038 patients. The AUC for ACAG (0.701, 95%CI: 0.652-0.749) was notably higher than that for anion gap and albumin. The Log-rank test revealed that the optimal cut-off point of ACAG for predicting in-hospital mortality was determined to be 20.375mmol/L. The multivariate Cox regression analysis demonstrated an independent association between high ACAG level and a higher risk of in-hospital mortality (HR = 3.128, 95% CI: 1.615-6.059). After PSM analysis, a matched cohort consisting of 291 subjects was obtained. We found no signifcant interaction in most stratas. Finally, The in-hospital, 30-day, and 90-day survival rates in the high ACAG group exhibited a statistically decrease compared to those in the low ACAG group both pre- and post-matching., Conclusion: The elevated level of ACAG was found to be independently associated with increased in-hospital mortality among trauma patients in the ICU., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With the increase of organic solid wastes (OSWs), current waste management practices, such as landfill, incineration, and windrow composting, have shown weaknesses in both resource recycling and environmental protection. Co-composting has been used to achieve nutrient and carbon recycling but is accused of high ammonia emission and low degradation efficiency. Therefore, this study developed a precision co-composting strategy (S3, which adds functional bacteria generated from food processing waste to a co-composting system) and compared it with the current OSW treatment strategy (S1) and traditional co-composting strategy (S2) from a life cycle assessment (LCA) perspective. The results showed that compared with S1, the eco-efficiency increased by 31.3% due to the higher economic profit of S2 but did not directly reduce the environmental cost. The addition of bacterial agents reduced ammonia emissions and shortened composting time, so compared with S1 and S2, the environmental cost of S3 was reduced by 37.9 and 43.6%, while the economic profit increased by 79.8 and 24.4%, respectively. The changes in environmental costs and economic benefits resulted in a huge improvement of S3's eco-efficiency, which was 189.6 and 121.7% higher than S1 and S2. Meanwhile, the adoption of S3 at a national scale in China could reduce the emission of 1,4-dichlorobenzene by 99.9% compared with S1 and increase profits by 6.58 billion USD per year. This study proposes a novel approach that exhibits high eco-efficiency in the treatment of OSWs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: This study aimed to develop a population pharmacokinetic (PopPK) model of ilaprazole in healthy subjects and patients with duodenal ulcer in Chinese and investigate the effect of potential covariates on pharmacokinetic (PK) parameters. Methods: Pharmacokinetic data from 4 phase I clinical trials and 1 phase IIa clinical trial of ilaprazole were included in PopPK analysis. Phoenix NLME 8.3 was used to establish a PopPK model and quantify the effects of covariate, such as demographic data, biochemical indicators and disease state on the PK parameters of ilaprazole. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and visual predictive check. Results: A two-compartment model with first-order elimination successfully described the pharmacokinetic properties of ilaprazole. In the final PopPK model, body weight and sex were identified as statistically significant covariates for volume of peripheral compartment (V p ) and clearance of central compartment (CL), respectively, and disease status was also screened as a significant covariate affecting both CL and V p . The validation results demonstrated the good predictability of the model, which was accurate and reliable. Conclusion: This is the first population pharmacokinetics study of ilaprazole in the Chinese, and the PopPK model developed in this study is expected to be helpful in providing relevant PK parameters and covariates information for further studies of ilaprazole., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Liu, Wu and Wang.)

Electroencephalography (EEG) is typical time-series data. Designing an automatic detection model for EEG is of great significance for disease diagnosis. For example, EEG stands as one of the most potent diagnostic tools for epilepsy detection. A myriad of studies have employed EEG to detect and classify epilepsy, yet these investigations harbor certain limitations. Firstly, most existing research concentrates on the labels of sliced EEG signals, neglecting epilepsy labels associated with each time step in the original EEG signal-what we term fine-grained labels. Secondly, a majority of these studies utilize static graphs to depict EEG's spatial characteristics, thereby disregarding the dynamic interplay among EEG channels. Consequently, the efficient nature of EEG structures may not be captured. In response to these challenges, we propose a novel seizure detection and classification framework-the dynamic temporal graph convolutional network (DTGCN). This method is specifically designed to model the interdependencies in temporal and spatial dimensions within EEG signals. The proposed DTGCN model includes a unique seizure attention layer conceived to capture the distribution and diffusion patterns of epilepsy. Additionally, the model incorporates a graph structure learning layer to represent the dynamically evolving graph structure inherent in the data. We rigorously evaluated the proposed DTGCN model using a substantial publicly available dataset, TUSZ, consisting of 5499 EEGs. The subsequent experimental results convincingly demonstrated that the DTGCN model outperformed the existing state-of-the-art methods in terms of efficiency and accuracy for both seizure detection and classification tasks.

We report the observation of hotspot-induced emitters and photoluminescence enhancement of up to 42-fold from DNA origami-assisted plasmonic dimer nanoantennas upon excess polarized laser illumination. The presence of DNA and laser polarization alignment along the dimer axis are critical for the generation of bright emitters responsible for the observed PL increase. The emission spectrum reveals characteristic Raman peaks of amorphous carbon, suggesting the formation of carbon-based emitters in the nanoantenna due to the plasmonic hotspots at the longitudinal antenna resonance.

Objective: This study amied to investigate the prognostic characteristics of triple negative breast cancer (TNBC) patients by analyzing B cell marker genes based on single-cell and bulk RNA sequencing., Methods: Utilizing single-cell sequencing data from TNBC patients, we examined tumor-associated B cell marker genes. Transcriptomic data from The Cancer Genome Atlas (TCGA) database were used as the foundation for predictive modeling. Independent validation set was conducted using the GSE58812 dataset. Immune cell infiltration into the tumor was assessed through various, including XCELL, TIMER, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, and ssGSEA. The TIDE score was utilized to predict immunotherapy outcomes. Additional investigations were conducted on the immune checkpoint blockade gene, tumor mutational load, and the GSEA enrichment analysis., Results: Our analysis encompassed 22,106 cells and 20,556 genes in cancerous tissue samples from four TNBC patients, resulting in the identification of 116 B cell marker genes. A B cell marker gene score (BCMG score) involving nine B cell marker genes ( ZBP1, SEL1L3 , CCND2, TNFRSF13C, HSPA6, PLPP5, CXCR4, GZMB , and CCDC50 ) was developed using TCGA transcriptomic data, revealing statistically significant differences in survival analysis ( P <0.05). Functional analysis demonstrated that marker genes were predominantly associated with immune-related pathways. Notably, substantial differences between the higher and lower- BCMG score groups were observed in terms of immune cell infiltration, immune cell activity, tumor mutational burden, TIDE score, and the expression of immune checkpoint blockade genes., Conclusion: This study has established a robust model based on B-cell marker genes in TNBC, which holds significant potential for predicting prognosis and response to immunotherapy in TNBC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Zhao, Xu, Lan, Lin, Wu and Li.)

Background: SYHA1807 is a novel lysine specific demethylase 1 inhibitor being developed for the treatment of small-cell lung cancer. Aim: This study aimed to establish a ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)/MS method for measuring SYHA1807 in human plasma, supporting its application in a first-in-human study. Methods: SYHA1807 was separated on an ACQUITY UPLC BEH ® C18 Column (2.1 × 50 mm, 1.7 μm) after protein precipitation of plasma samples. Mass spectrometry analysis was performed with a Xevo TQS triple quadrupole mass spectrometer utilizing a positive electronic spray ionization source. The established method was fully validated according to bioanalytical guidelines. Results & conclusion: A rapid, specific and robust UPLC-MS/MS method was first established for quantifying SYHA1807 and successfully applied in a first-in-human study.

Plasmonic nanoparticle arrays with a specific lattice arrangement can support surface lattice resonances (SLRs). SLR exhibits a sharp spectral peak and finds many applications including optical sensing and plasmonic lasers. To optimize SLR for application, a robust method that allows the mass production of plasmonic nanoparticle arrays with refined particle morphology and well-defined lattice arrangement is required. In this work, we combine nanosphere lithography (NSL) with thermal annealing or nanosecond-pulsed laser treatment to refine plasmonic nanoparticles in a honeycomb lattice. We comparatively study the effects of the two treatment methods on the particle morphology and lattice arrangement of mono (Ag and Pd) and bi-metallic (Ag-Pd) nanoparticle lattices. In general, thermal annealing preserves the lattice arrangement but fairly changes the particle roundness, while laser treatment produces particles with varying morphologies and spatial distribution. We also theoretically and experimentally investigate the optical responses of Ag nanoparticle lattices produced by different treatment methods. The observed difference in spectra can be attributed to the varying particle morphology, which shifts the localized surface plasmon resonance differently, resulting in a significant change in SLR. These findings provide valuable insights for optimizing plasmonic nanoparticle arrays for various applications.

Future food farming technology faces challenges that must integrate the core goal of keeping the global temperature increase within 1.5 °C without reducing food security and nutrition. Here, we show that boosting the production of insects and earthworms based on food waste and livestock manure to provide food and feed in China will greatly contribute to meeting the country's food security and carbon neutrality pledges. By substituting domestic products with mini-livestock (defined as earthworms and insects produced for food or feed) protein and utilizing the recovered land for bioenergy production plus carbon capture and storage, China's agricultural sector could become carbon-neutral and reduce feed protein imports to near zero. This structural change may lead to reducing greenhouse gas emissions by 2,350 Tg CO 2 eq per year globally when both domestic and imported products are substituted. Overall, the success of mini-livestock protein production in achieving carbon neutrality and food security for China and its major trading partners depends on how the substitution strategies will be implemented and how the recovered agricultural land will be managed, e.g., free use for afforestation and bioenergy or by restricting this land to food crop use. Using China as an example, this study also demonstrates the potential of mini-livestock for decreasing the environmental burden of food production in general.

Optical quantum emitters near nanostructures have access to additional relaxation channels and thus exhibit structure-dependent emission properties, including quantum yield and emission directionality. A well-engineered quantum emitter-plasmonic nanostructure hybrid can be considered as an optical meta-emitter consisting of a transmitting nanoantenna driven by an optical-frequency generator. In this work, the DNA origami fabrication method is used to construct ultracompact unidirectional meta-emitters composed of a plasmonic trimer nanoantenna driven by a single dye molecule. The origami is designed to bring the dye to the gap to simultaneously excite the electric and magnetic dipole modes of the trimer nanoantenna. The interference of these modes fulfills the Kerker condition at the fluorophore's emission band, enabling unidirectional emission. We report unidirectional emission from a single molecule with a front-to-back ratio of up to 10.7 dB accompanied by a maximum emission enhancement of 23-fold.

Purpose: Some patients experience sleep disturbances after endoscopy performed under sedation. This study aimed to evaluate the effects of propofol on sleep quality after gastrointestinal endoscopy (GE)., Design: This study was a prospective cohort study., Methods: This study enrolled 880 patients who underwent GE. Patients who chose to undergo GE under sedation received intravenous propofol, whereas the control group did not. The Pittsburgh Sleep Quality Index (PSQI) was measured before GE (PSQI-1) and 3 weeks (PSQI-2) after GE. The Groningen Sleep Score Scale (GSQS) was used before GE (GSQS-1) and 1 (GSQS-2) and 7 days (GSQS-3) after GE., Findings: There was a significant increase in GSQS scores from baseline to days 1 and 7 after GE (GSQS-2 vs GSQS-1, P < .001, GSQS-3 vs GSQS-1, P = .008). However, no significant changes were observed in the control group (GSQS-2 vs GSQS-1, P = .38, GSQS-3 vs GSQS-1, P = .66). On day 21, there were no significant changes in the baseline PSQI scores over time in either group (sedation group, P = .96; control group, P = .95)., Conclusions: GE with propofol sedation negatively affected sleep quality for 7 days after GE but not 3 weeks after GE., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Aficamten is a selective, small-molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of aficamten in healthy adults. Methods: This double-blind, randomized, placebo-controlled, phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and multi-dose (MD) administrations of aficamten. In the SAD cohort, 16 participants were randomized to receive a single oral dose of aficamten: 10 mg, 20 mg, or placebo. In the MD cohort, 12 participants were randomized to receive multiple doses of aficamten: 5 mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests, and reporting of adverse events (AEs). Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact, were evaluated. Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose-proportional over the dose range of 5-20 mg and accumulated in the MD cohort. Conclusion: Aficamten was safe and well-tolerated in the healthy Chinese adult participants. The pharmacokinetics of aficamten in the Chinese population was comparable to those previously found in Western participants. These phase 1 data support the progression of aficamten into future clinical studies in Chinese patients. Clinical Trial registration: https://clinicaltrials.gov, identifier: NCT04783766., Competing Interests: Authors JL, YL, BL, YH, XC, and YL were employed by the company Ji Xing Pharmaceuticals (Shanghai) Co., Ltd., and author DX was employed by the company Cytokinetics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Liu, Tian, Fang, Yu, Wu, Liu, Wan, Li, Luo, Li, Liu, He, Chen, Li, Xu, Wang and Han.)

Background: Children and young people's mental health is a growing public health concern, which is further exacerbated by the COVID-19 pandemic. Mobile health apps, particularly those using passive smartphone sensor data, present an opportunity to address this issue and support mental well-being., Objective: This study aimed to develop and evaluate a mobile mental health platform for children and young people, Mindcraft, which integrates passive sensor data monitoring with active self-reported updates through an engaging user interface to monitor their well-being., Methods: A user-centered design approach was used to develop Mindcraft, incorporating feedback from potential users. User acceptance testing was conducted with a group of 8 young people aged 15-17 years, followed by a pilot test with 39 secondary school students aged 14-18 years, which was conducted for a 2-week period., Results: Mindcraft showed encouraging user engagement and retention. Users reported that they found the app to be a friendly tool helping them to increase their emotional awareness and gain a better understanding of themselves. Over 90% of users (36/39, 92.5%) answered all active data questions on the days they used the app. Passive data collection facilitated the gathering of a broader range of well-being metrics over time, with minimal user intervention., Conclusions: The Mindcraft app has shown promising results in monitoring mental health symptoms and promoting user engagement among children and young people during its development and initial testing. The app's user-centered design, the focus on privacy and transparency, and a combination of active and passive data collection strategies have all contributed to its efficacy and receptiveness among the target demographic. By continuing to refine and expand the app, the Mindcraft platform has the potential to contribute meaningfully to the field of mental health care for young people., (©Balasundaram Kadirvelu, Teresa Bellido Bel, Xiaofei Wu, Victoria Burmester, Shayma Ananth, Bianca Cabral C C Branco, Braulio Girela-Serrano, Julia Gledhill, Martina Di Simplicio, Dasha Nicholls, A Aldo Faisal. Originally published in JMIR Formative Research (https://formative.jmir.org), 26.06.2023.)

Tigecycline, a tetracycline antibiotic, is widely used against antimicrobial resistance; therefore, medical staff should use tigecycline rationally to improve clinical efficacy and reduce resistance to this drug. The present study aimed to enhance the rate of rational tigecycline usage. The patients were divided into a low-dose (50 mg tigecycline twice daily, every 12 h) and a high-dose group (100 mg twice daily, every 12 h). The blood concentrations of tigecycline were examined and the area under the curve (AUC) 0-12 h values of the two groups were calculated. Prescriptions of tigecycline for 40 intensive care unit (ICU) cases were reviewed to evaluate the rationality of tigecycline usage. The peak plasma concentrations (the 7th administration after 1 h) of tigecycline were significantly higher in the high-dose group (2.46±0.43 µg/ml) compared with those in the low-dose group (1.25±0.16 µg/ml). The AUC 0-12 h was 16.35±3.09 h µg/ml in the high-dose group and 9.83±1.23 h µg/ml in the low-dose group (P<0.001). There were 29 irrational prescriptions identified, involving: i) Lack of consultation records (n=20); ii) inappropriate usage or dosage (n=17); iii) inappropriate drug selection (n=2); or iv) lack of dynamic laboratory tests to evaluate the efficacy (n=4). The irrational use of tigecycline in ICU patients is common. The rate of rational tigecycline usage can be improved by strengthening the management, training and participation of clinical pharmacists., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yu et al.)

This work developed a series of siloxane-modified polyurethane (PU-Si) containing ordered hard segments by a facile method. The polyaddition between poly(ε-caprolactone) and excess diurethane diisocyanate was carried out to synthesize a polyurethane prepolymer with terminal isocyanate groups, which was then end-capped by 3-aminopropyl triethoxysilane to produce alkoxysilane-terminated polyurethane; the target products of PU-Si were obtained with hydrolysis and the condensation of alkoxysilane groups. The chemical structures were confirmed by FT-IR and XPS, and the effect of the siloxane content or cross-linked degree on the physicochemical properties of the PU-Si films was investigated in detail. The formation of the network structure linked by Si-O-Si bonds and interchain denser hydrogen bonds endowed PU-Si films with fine phase compatibility, low crystallinity, high thermal stability, and excellent tensile properties. Due to the high cross-linked degree and low interfacial energy, the films displayed a high surface water contact angle and low equilibrium water absorption, which resulted in slow hydrolytic degradation rates. Furthermore, the evaluation of protein adsorption and platelet adhesion on the PU-Si film surface presented high resistance to biofouling, indicating superior surface biocompatibility. Consequently, the siloxane-cross-linked polyurethane, which possessed excellent tensile properties, high biostability, and superior biocompatibility, showed great potential to be explored as biomaterials for durable implants.

Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.

To evaluate the influence of solubility and permeability on the pharmacokinetic prediction performance of orally administered drugs using avirtual bioequivalence (VBE) model, a total of 23 orally administered drugs covering Biopharmaceutics Classification System (BCS) classes 1-4 were selected. A VBE model (i.e., a physiologically based pharmacokinetic model integrated with dissolution data) based on a B 2 O simulator was applied for pharmacokinetic (PK) prediction in a virtual population. Parameter sensitivity analysis was used for input parameter selection. The predictive performances of PK parameters (i.e., AUC 0- t , C max , and T max ), PK profiles, and bioequivalence (BE) results were evaluated using the twofold error, average fold error (AFE), absolute average fold error (AAFE), and BE reassessment metrics. All models successfully simulated the mean PK profiles, with AAFE < 2 and AFE ranging from 0.58 to 1.66. As for the PK parameters, except for the time of peak concentration, T max , of isosorbide mononitrate, other simulated PK parameters were all within a twofold error. The simulated PK behaviors were comparable to the observed ones, both for test ( T ) and reference ( R ) products, and the simulated T / R arithmetic mean ratios were all within 0.88-1.16 of the observed values. These four evaluation metrics were distributed equally among BCS class 1-4 drugs. The VBE model showed powerful performance to predict the PK behavior of orally administered drugs with various combinations of solubility and permeability, irrespective of the BCS category.

Plasmonic gratings are simple and effective platforms for nonlinear signal generation since they provide a well-defined momentum for photon-plasmon coupling and local hot spots for frequency conversion. Here, a plasmonic azimuthally chirped grating (ACG), which provides spatially resolved broadband momentum for photon-plasmon coupling, was exploited to investigate the plasmonic enhancement effect in two nonlinear optical processes, namely two-photon photoluminescence (TPPL) and second harmonic generation (SHG). The spatial distributions of the nonlinear signals were determined experimentally by hyperspectral mapping with ultrashort pulsed excitation. The experimental spatial distributions of nonlinear signals agree very well with the analytical prediction based on photon-plasmon coupling with the momentum of the ACG, revealing the "antenna" function of the grating in plasmonic nonlinear signal generation. This work highlights the importance of the antenna effect of the gratings for nonlinear signal generation and provides insight into the enhancement mechanism of plasmonic gratings in addition to local hot spot engineering.

Gold nanoparticles (AuNPs) with interesting optical properties have attracted much attention in recent years. The synthesis and plasmonic properties of AuNPs with a controllable size and shape have been extensively investigated. Among these AuNPs, gold nanotriangles (AuNTs) exhibited unique optical and plasmonic properties due to their special triangular anisotropy. Indeed, AuNTs showed promising applications in optoelectronics, optical sensing, imaging and other fields. However, only few reviews about these applications have been reported. Herein, we comprehensively reviewed the synthesis and self-assembly of AuNTs and their applications in recent years. The preparation protocols of AuNTs are mainly categorized into chemical synthesis, biosynthesis and physical-stimulus-induced synthesis. The comparison between the advantages and disadvantages of various synthetic strategies are discussed. Furthermore, the specific surface modification of AuNTs and their self-assembly into different dimensional nano- or microstructures by various interparticle interactions are introduced. Based on the unique physical properties of AuNTs and their assemblies, the applications towards chemical biology and sensing were developed. Finally, the future development of AuNTs is prospected.

What Is Known and Objective: To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug-resistant bacteria (MDRB) infections., Methods: Blood/sputum samples were collected at intervals after tigecycline had reached a steady-state. Tigecycline concentrations in specimens were determined by high-performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non-compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000-patient Monte Carlo Simulation., Results: In plasma, the maximum concentration (C max ) and area under the concentration-time curve from 0 to 12 h (AUC 0-12h ) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 h mg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 h mg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4 mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8 mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria., What Is New and Conclusion: In this study, we explored PK/PD of high-dose tigecycline in plasma and sputum. From a PK/PD perspective, high-dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial-drug concentrations should be determined to optimize their clinical use., (© 2022 John Wiley & Sons Ltd.)

Conflict adaptation is of particular importance to human information processing, as it assists in efficient responding when confronted with inconsistent information. Past investigators have focused on the role and mechanisms of conflict adaptation effects in cognitive control tasks, but there have been few studies of conflict adaptation effects in numerical inductive reasoning. In this study we adopted identical, perceptual mismatch and rule violation conditions to investigate conflict adaptation in numerical inductive reasoning. Behaviorally, we found shorter response times on trials following our experimental condition, as compared to pre-trials. In our event-related potential (ERP) electroencephalogram (EEG) results, N2 reflected the improvement in processing efficiency of rule violations in numerical inductive reasoning. Thus, these data suggest the presence of a conflict adaptation effect in high-level processing.

Purpose: This study aims to evaluate the potential of C-reactive protein to lymphocyte count ratio (CLR) for the prediction of surgical site infection (SSI) following posterior lumbar interbody fusion (PLIF) and the instrumentation of lumbar degenerative diseases., Methods: In this retrospective study, we considered patients with a lumbar degenerative disease diagnosis surgically treated by the instrumented PLIF procedure from 2015 to 2021. Patient data, including postoperative early SSI and other perioperative variables, were collected from their respective hospitalization electronic medical records. The receiver operator characteristic curve was constructed to determine the optimal cut-off value for CLR, and the ability to predict SSI was evaluated by the area under the curve (AUC). According to the cut-off value, patients were dichotomized with high- or low-CLR, and between-group differences were compared using univariate analysis. The independent impact of CLR on predicting SSI was investigated by multivariate logistics regression analysis., Results: A total of 773 patients were included, with 26 (3.4%) developing an early SSI post-operation. The preoperative CLR was 11.1 ± 26.1 (interquartile range, 0.4-7.5), and the optimal cut-off was 2.1, corresponding to a sensitivity of 0.856, a specificity of 0.643, and an AUC of 0.768 (95% CI, 0.737-0.797). CLR demonstrated a significantly improved prediction ability than did lymphocyte count ( P  = 0.021) and a similar ability to predict an infection as C-response protein ( P  = 0.444). Patients with a high CLR had a significantly higher SSI incidence than those with a low CLR (7.6% vs. 0.8%, P  < 0.001). After adjustment for numerous confounding factors, CLR ≥ 2.1 was associated with an 11.16-fold increased risk of SSI, along with other significant variables, i.e., diabetes, preoperative waiting time, and surgical duration., Conclusion: A high CLR exhibited an improved ability to predict incident SSI and was associated with a substantially increased risk of SSI following instrumented PLIF. After better-design studies verified this finding, CLR could potentially be a beneficial tool in surgical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Wu, Ma, Zhu and Chen.)

Background: Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare disorder mainly involved in ocular movement and spinal development. It is caused by a roundabout guidance receptor 3 ( ROBO3 ) gene mutation. This study aimed to describe the clinical features of six patients with HGPPS and investigate the corresponding ROBO3 gene mutations., Methods: Patients underwent detailed clinical and imaging examinations. Whole-exome sequencing was performed to detect nucleotide variations in the disease-causing genes of HGPPS., Results: Six pathogenic variants were detected in the ROBO3 gene from six patients with HGPPS, including two novel compound heterozygous mutations, c.1447C > T (p.R483X) and c.2462G > C (p.R821P); c.1033G > C (p.V345L) and c.3287G > T (p.C1096F); a novel homozygous indel mutation, c.565dupC (p.R191Pfs*61); and a known missense mutation, c.416G > T (p.G139V). Patients with HGPPS had horizontal conjugated eye movement defects and scoliosis with variable degrees, as well as flattened pontine tegmentum and uncrossed corticospinal tracts on magnetic resonance imaging., Conclusion: Our genetic findings will expand the spectrum of ROBO3 mutations and help inform future research on the molecular mechanism of HGPPS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Guo, Xie, Zhou, Wu, Li, Peng and Li.)

In recent years, the research and development (R&D) of innovative drugs in China has been dramatically accelerated. And the early clinical study is crucial for drug R&D. However, little is known involving the change of phase I trials for noncancer drugs. We retrieved the data of phase I clinical trials for noncancer innovative drugs on the Registration and Information Disclosure Platform for Drug Clinical Studies on the Center for Drug Evaluation. The number of clinical trials proliferating in recent years and the average annual growth rates of chemical and biological drugs were 55.5% and 42.1%, respectively. Most trials were distributed in Beijing, Shanghai, and other developed coastal cities. Moreover, the clinical trials of innovative drugs in China were focused on the digestive and endocrine systems, whereas the pediatric and orphan drugs were scarce. Based on the data assessment, this work provided comprehensive analysis and suggestions about Chinese drug R&D. Significant advancement has been made in mainland China with the implementation of available policies and the emergence of advanced technologies. Though shortcomings, including uneven geographic distribution and lack of pediatric and orphan drugs, still exist, we believe progress will continue to be made in mainland China., (© 2022, The American College of Clinical Pharmacology.)

Aims: Our team tested spinal cord fusion (SCF) using the neuroprotective agent polyethylene glycol (PEG) in different animal (mice, rats, and beagles) models with complete spinal cord transection. To further explore the application of SCF for the treatment of paraplegic patients, we developed a new clinical procedure for SCF called vascular pedicle hemisected spinal cord transplantation (vSCT) and tested this procedure in eight paraplegic participants., Methods: Eight paraplegic participants (American Spinal Injury Association, ASIA: A) were enrolled and treated with vSCT (PEG was applied to the sites of spinal cord transplantation). Pre- and postoperative pain intensities, neurologic assessments, electrophysiologic monitoring, and neuroimaging examinations were recorded., Results: Of the eight paraplegic participants who completed vSCT, objective improvements occurred in motor function for one participant, in electrophysiologic motor-evoked potentials for another participant, in re-establishment of white matter continuity in three participants, in autonomic nerve function in seven participants, and in symptoms of cord central pain for seven participants., Conclusions: The postoperative recovery of paraplegic participants demonstrated the clinical feasibility and efficacy of vSCT in re-establishing the continuity of spinal nerve fibers. vSCT could provide the anatomic, morphologic, and histologic foundations to potentially restore the motor, sensory, and autonomic nervous functions in paraplegic patients. More future clinical trials are warranted., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)