Mechanism of action of the Banxia-Xiakucao herb pair in sleep deprivation: New comprehensive evidence from network pharmacology, transcriptomics and molecular biology experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herb pairs are the most basic and compressed examples of Chinese herbal combinations and can be used to effectively explain the fundamental concepts of traditional Chinese medicine prescriptions. These pairings have gained significant interest due to their subtle therapeutic benefits, minimal side effects, and efficacy in treating complicated chronic conditions. The Banxia-Xiakucao Chinese herb pair (BXHP) consists of Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao). This formula was documented in The Medical Classic of the Yellow Emperor approximately 2000 years ago，and clinical research has demonstrated that BXHP effectively treats insomnia. AIM OF THE STUDY: This study aimed to evaluate the efficacy and therapeutic mechanism of the BXHP through a comprehensive strategy involving network pharmacology, molecular docking, transcriptomics, and molecular biology experimental validation. MATERIALS AND METHODS: The composition of BXHP was characterized using the UPLC-Q-TOF-MS. The active compounds were screened to find drug-likeness compounds by analyzing the ADME data. To predict the molecular mechanism of BXHP in sleep deprivation (SD) by network pharmacology and molecular docking. We established a rat model of SD and the in vivo efficacy of BXHP was verified through the pentobarbital sodium righting reflex test, behavioral assays, enzyme-linked immunosorbent assay, transmission electron microscopy, HE staining, and Nissl staining, and the underlying molecular mechanism of BXHP in SD was revealed through transcriptomic and bioinformatic analyses in conjunction with quantitative real-time PCR, Western blot, and immunofluorescence staining. RESULTS: In the present study, we showed for the first time that BXHP reduced sleep latency, prolongs sleep duration, and improves anxiety; lowered serum CORT, IL6, TNF-α and MDA levels; decreased hypothalamic Glu levels; and elevated hypothalamic GABA and 5-HT levels in SD rats. We found 16 active compounds that acted on 583 targets, 145 of which are related to SD. By modularly dissecting the PPI network, we discovered three critical targets, Akt1, CREB1, and PRKACA, all of which play important roles in the effects of BXHP on SD. Molecular docking resulted in the identification of 16 active compounds that strongly bind to key targets. The results of GO and KEGG enrichment analyses of network pharmacology and transcriptomics focused on both the regulation of circadian rhythm and the cAMP signaling pathway, which strongly demonstrated that BXHP affects SD via the cAMP-PKA-CREB-Circadian rhythm pathway. Molecular biology experiments verified this hypothesis. Following BXHP administration, PKA and CREB phosphorylation levels were elevated in SD rats, the cAMP-PKA-CREB signaling pathway was activated, the expression levels of the biological clock genes CLOCK, p-BMAL1/BMAL1, and PER3 were increased, and the rhythmicity of the biological clock was improved. CONCLUSIONS: The active compounds in BXHP can activate the cAMP-PKA-CREB-Circadian rhythm pathway, improve the rhythmicity of the biological clock, promote sleep and ameliorate anxiety, which suggests that BXHP improves SD through a multicomponent, multitarget, multipathway mechanism. This study is important for the development of herbal medicines and clinical therapies for improving sleep deprivation.

Physical activity promotes brain development through serotonin during early childhood.

Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta-analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood.

A Review on Autism Spectrum Disorder Screening by Artificial Intelligence Methods.

PURPOSE: With the increasing prevalence of autism spectrum disorders (ASD), the importance of early screening and diagnosis has been subject to considerable discussion. Given the subtle differences between ASD children and typically developing children during the early stages of development, it is imperative to investigate the utilization of automatic recognition methods powered by artificial intelligence. We aim to summarize the research work on this topic and sort out the markers that can be used for identification. METHODS: We searched the papers published in the Web of Science, PubMed, Scopus, Medline, SpringerLink, Wiley Online Library, and EBSCO databases from 1st January 2013 to 13th November 2023, and 43 articles were included. RESULTS: These articles mainly divided recognition markers into five categories: gaze behaviors, facial expressions, motor movements, voice features, and task performance. Based on the above markers, the accuracy of artificial intelligence screening ranged from 62.13 to 100%, the sensitivity ranged from 69.67 to 100%, the specificity ranged from 54 to 100%. CONCLUSION: Therefore, artificial intelligence recognition holds promise as a tool for identifying children with ASD. However, it still needs to continually enhance the screening model and improve accuracy through multimodal screening, thereby facilitating timely intervention and treatment.

Prescription glucocorticoid medication and iridocyclitis are associated with an increased risk of senile cataract occurrence: a Mendelian randomization study.

Iridocyclitis and the use of glucocorticoid medication have been widely studied as susceptibility factors for cataracts. However, the causal relationship between them remains unclear. This study aimed to investigate the causal relationship between the development of iridocyclitis and the genetic liability of glucocorticoid medication use on the risk of senile cataracts occurrence by performing Two-sample Mendelian randomization (MR) analyses. Instrumental variables (IVs) significantly associated with exposure factors (P < 5 × 10-8) were identified using published genome-wide association data from the FinnGen database and UK Biobank. Reliability analyses were conducted using five approaches, including inverse-variance weighted (IVW), MR-Egger regression, simple median, weighted median, and weighted mode. A sensitivity analysis using the leave-one-out method was also performed. Genetic susceptibility to glucocorticoid use was associated with an increased risk of developing senile cataracts (OR, 1.10; 95% CI, 1.02-1.17; P < 0.05). Moreover, iridocyclitis was significantly associated with a higher risk of developing senile cataracts (OR, 1.03; 95% CI, 1.01-1.05; P < 0.05). Nonetheless, some heterogeneity in the IVs was observed, but the MR results remained consistent after penalizing for outliers. The estimates were consistent in multivariate analyses by adjusting for body mass index (BMI) and diabetes mellitus type 2 (T2DM). This study provides new insights into the prevention and management of senile cataracts by highlighting the increased risk associated with iridocyclitis and the use of glucocorticoids.

Enhancing biohydrogen production from xylose at low temperature (20 °C) using natural FeS2 Ore: Thermodynamic analysis and mechanistic insights.

This study investigates the efficacy of pyrite in enhancing biohydrogen production from xylose at low temperature (20 °C). Higher hydrogen yield rates (Rm) and reduced lag time (λ) were achieved across initial xylose concentrations ranging from 2-10 g/L. At an optimal xylose concentration of 5 g/L, pyrite reduced λ by 2.5 h and increased Rm from 1.3 to 2.7 mL h-1. These improvements are attributed to pyrite's ability to enhance the secretion of extracellular polymeric substance and flavins, facilitate NADH and NAD+ generation and transition, and favor biohydrogen production. Thermodynamic analyses and Gibbs free energy calculations further elucidated pyrite's role in the full reaction process and rate-limiting steps at low temperature. This study offers valuable insights into improving the efficiency of biohydrogen production at low temperature, with significant implications for energy conservation.

GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

MaHsf24, a novel negative modulator, regulates cold tolerance in banana fruits by repressing the expression of HSPs and antioxidant enzyme genes.

Transcriptional regulation mechanisms underlying chilling injury (CI) development have been widely investigated in model plants and cold-sensitive fruits, such as banana (Musa acuminata). However, unlike the well-known NAC and WRKY transcription factors (TFs), the function and deciphering mechanism of heat shock factors (HSFs) involving in cold response are still fragmented. Here, we showed that hot water treatment (HWT) alleviated CI in harvested banana fruits accomplishing with reduced reactive oxygen species (ROS) accumulation and increased antioxidant enzyme activities. A cold-inducible but HWT-inhibited HSF, MaHsf24, was identified. Using DNA affinity purification sequencing (DAP-seq) combined with RNA-seq analyses, we found three heat shock protein (HSP) genes (MaHSP23.6, MaHSP70-1.1 and MaHSP70-1.2) and three antioxidant enzyme genes (MaAPX1, MaMDAR4 and MaGSTZ1) were the potential targets of MaHsf24. Subsequent electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) and dual-luciferase reporter (DLR) analyses demonstrated that MaHsf24 repressed the transcription of these six targets via directly binding to their promoters. Moreover, stably overexpressing MaHsf24 in tomatoes increased cold sensitivity by suppressing the expressions of HSPs and antioxidant enzyme genes, while HWT could recover cold tolerance, maintaining higher levels of HSPs and antioxidant enzyme genes, and activities of antioxidant enzymes. In contrast, transiently silencing MaHsf24 by virus-induced gene silencing (VIGS) in banana peels conferred cold resistance with the upregulation of MaHSPs and antioxidant enzyme genes. Collectively, our findings support the negative role of MaHsf24 in cold tolerance, and unravel a novel regulatory network controlling bananas CI occurrence, concerning MaHsf24-exerted inhibition of MaHSPs and antioxidant enzyme genes.

Cell-free DNA methylation patterns in aging and their association with inflamm-aging.

Aim: Liquid biopsies analyzing cell-free DNA (cfDNA) methylation in plasma offer a noninvasive diagnostic for diseases, with the potential of aging biomarkers underexplored. Methods: Utilizing enzymatic methyl-seq (EM-seq), this study assessed cfDNA methylation patterns in aging with blood from 35 healthy individuals. Results: It found aging signatures, including higher cfDNA levels and variations in fragment sizes, plus approximately 2000 age-related differentially methylated CpG sites. A biological age predictive model based on 48 CpG sites showed a strong correlation with chronological age, verified by two datasets. Age-specific epigenetic shifts linked to inflammation were revealed through differentially methylated regions profiling and Olink proteomics. Conclusion: These findings suggest cfDNA methylation as a potential aging biomarker and might exacerbate immunoinflammatory reactivity in older individuals.

Our bodies undergo many changes as we age, some of which might affect our health. To better understand these changes, scientists study something called 'cell-free DNA' (cfDNA) in our blood. This cfDNA can give us clues about our health and the risk of diseases like cancer or heart conditions.In our research, we analyzed cfDNA from the blood of 35 people to identify patterns associated with aging. We discovered that approximately 2000 specific spots in our DNA change in a way that's linked to aging. These changes might help us figure out someone's biological age ­ essentially, how old their body seems based on various health factors, which can differ from their actual age.We also found that these DNA changes could indicate how aging might make the body's defense system ­ which fights off diseases ­ react more intensely. Understanding this could be crucial for managing health as we get older.Our study suggests that cfDNA could be a useful marker for aging, offering a new approach to understanding and possibly managing the health effects associated with growing older.

In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals.

Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.

Challenges and Suggestions of Ethical Review on Clinical Research Involving Brain-Computer Interfaces.

Brain-computer interface (BCI) technology is rapidly advancing in medical research and application. As an emerging biomedical engineering technology, it has garnered significant attention in the clinical research of brain disease diagnosis and treatment, neurological rehabilitation, and mental health. However, BCI also raises several challenges and ethical concerns in clinical research. In this article, the authors investigate and discuss three aspects of BCI in medicine and healthcare: the state of international ethical governance, multidimensional ethical challenges pertaining to BCI in clinical research, and suggestive concerns for ethical review. Despite the great potential of frontier BCI research and development in the field of medical care, the ethical challenges induced by itself and the complexities of clinical research and brain function have put forward new special fields for ethics in BCI. To ensure "responsible innovation" in BCI research in healthcare and medicine, the creation of an ethical global governance framework and system, along with special guidelines for cutting-edge BCI research in medicine, is suggested.

Effect of prone positioning ventilation on pulmonary function in neonates during venous-arterial extracorporeal membrane oxygenation.

Background: The use of extracorporeal membrane oxygenation (ECMO) technology has significantly decreased mortality rates associated with neonatal pulmonary hypertension and respiratory failure. Prone positioning ventilation (PPV) is a commonly used technique in critically ill infants, designed to improve thoracic pressure gradients, re-expand dorsal lung segments, and increase oxygenation in approximately 70-80% of patients suffering from acute respiratory distress syndrome. This study aimed to evaluate the effects of PPV on pulmonary function in neonates undergoing venous-arterial extracorporeal membrane oxygenation (VA-ECMO). Methods: We conducted a retrospective analysis of clinical data from 17 neonates who received ECMO support in our institution, divided into two groups based on ventilation strategy: ECMO with PPV (ECMO-PPV, n=8) and ECMO with supine positioning ventilation (ECMO-SPV, n=9). Parameters such as the P/F ratio [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2)], oxygenation index (OI), respiratory system compliance (Crs), and airway resistance (RAW) were collected and analyzed at baseline, and at 1, 2, and 3 days post-ECMO initiation. In the ECMO-PPV group, these parameters were also assessed 3 days pre-treatment and 2 hours post-treatment initiation. Results: Initial comparisons between ECMO-PPV and ECMO-SPV groups showed no significant difference in PaO2/FiO2, OI, Crs, or RAW. Throughout the ECMO treatment, both groups demonstrated gradual improvements in PaO2/FiO2 and Crs, and reductions in OI and RAW. Notably, by day 3, the ECMO-PPV group exhibited significant improvements in Crs and RAW compared to the ECMO-SPV group (P<0.05). Specifically, in the ECMO-PPV group, Crs significantly increased and RAW decreased after 2 hours of initiating PPV, with these changes becoming statistically significant by day 3 (Crs P=0.03, RAW P=0.03). No severe PPV-related complications were noted. Conclusions: PPV during neonatal ECMO may improve respiratory compliance and reduce RAW, potentially aiding lung recovery. Our findings suggest PPV as a viable strategy for neonates under ECMO support.

Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway.

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.

Pain symptoms are associated with two-point discrimination threshold in patients with temporomandibular disorders.

OBJECTIVE: This study aimed to explore the associations of orofacial two-point discrimination (2-PD) test result with pain symptoms and psychological factors in patients with Temporomandibular Disorders (TMDs). METHODS: 193 patients with TMDs were included in this study. Patients' demographics, pain intensity, and psychological status were recorded. The 2-PDs in the bilateral temporal, zygomatic, mandibular, and temporomandibular joint (TMJ) regions of the patients were measured. Statistical analyses were conducted to observe the associations between variables. RESULTS: For Pain-related TMDs (PT) patients, Monthly Visual Analogue Scale (VAS-M) and Current Analogue Scale (VAS-C) were correlated with TMJ, zygomatic and temporal 2-PDs. Patients with PT tended to have higher TMJ 2-PDs[Right: ß = 1.827 mm, 95%CI(0.107, 3.548), P = 0.038], zygomatic 2-PDs[Right: ß = 1.696 mm, 95%CI(0.344, 3.048), P = 0.014], temporal 2-PDs[Left: ß = 2.138 mm, 95%CI(0.127, 4.149), P = 0.037; Right: ß = 1.893 mm, 95%CI(0.011, 3.775), P = 0.049]. Associations were also observed between VAS-C and TMJ 2-PDs[Left: ß = 0.780, 95%CI(0.190, 1.370), P = 0.01; Right: ß = 0.885, 95%CI(0.406, 1.364), P = 0.001], Zygomatic 2-PDs[Right: ß = 0.555, 95%CI(0.172, 0.938), P = 0.005]; VAS-M and TMJ 2-PDs[Left: ß = 0.812, 95%CI(0.313, 1.311), P = 0.002; Right: ß = 0.567, 95%CI(0.152, 0.983), P = 0.008], zygomatic 2-PDs[Left: ß = 0.405, 95%CI(0.075, 0.735), P = 0.016; Right: ß = 0.545, 95%CI(0.221, 0.870), P = 0.001], and temporal 2-PDs [Left: ß = 0.741, 95%CI(0.258, 1.224), P = 0.003; Right: ß = 0.519, 95%CI(0.063, 0.975), P = 0.026]. CONCLUSION: TMJ, zygomatic, and temporal 2-PDs were significantly associated with PT and pain intensity. Age, gender and psychological factors were not associated with orofacial 2-PDs. PT patients exhibited weaker tactile acuity compared to Non-PT patients. Further discussion on the underlying mechanism is needed. CLINICAL RELEVANCE: Orofacial tactile acuity of TMDs patients was associated with their pain symptoms, which researchers should take account into when performing 2-PD tests for TMDs patients. The 2-PD test can be considered as a potential tool along with the current procedures for the differentiations of PT and Non-PT.

Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis.

Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1-64 µM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1 µM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25 µM), necroptosis inhibitor necrostatin-1 (10 µM), or pan-caspase inhibitor Z-VAD-FMK (10 µM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5-30 µM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20 mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.

Energy-efficient superparamagnetic Ising machine and its application to traveling salesman problems.

The growth of artificial intelligence leads to a computational burden in solving non-deterministic polynomial-time (NP)-hard problems. The Ising computer, which aims to solve NP-hard problems faces challenges such as high power consumption and limited scalability. Here, we experimentally present an Ising annealing computer based on 80 superparamagnetic tunnel junctions (SMTJs) with all-to-all connections, which solves a 70-city traveling salesman problem (TSP, 4761-node Ising problem). By taking advantage of the intrinsic randomness of SMTJs, implementing global annealing scheme, and using efficient algorithm, our SMTJ-based Ising annealer outperforms other Ising schemes in terms of power consumption and energy efficiency. Additionally, our approach provides a promising way to solve complex problems with limited hardware resources. Moreover, we propose a cross-bar array architecture for scalable integration using conventional magnetic random-access memories. Our results demonstrate that the SMTJ-based Ising computer with high energy efficiency, speed, and scalability is a strong candidate for future unconventional computing schemes.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Three-dimensional laser micromachining system with integrated sub-100†nm resolution in-situ measurement.

In this study, a three-dimensional (3D) laser micromachining system with an integrated sub-100 nm resolution in-situ measurement system was proposed. The system used the same femtosecond laser source for in-situ measurement and machining, avoiding errors between the measurement and the machining positions. It could measure the profile of surfaces with an inclination angle of less than 10°, and the measurement resolution was greater than 100 nm. Consequently, the precise and stable movement of the laser focus could be controlled, enabling highly stable 3D micromachining. The results showed that needed patterns could be machined on continuous surfaces using the proposed system. The proposed machining system is of great significance for broadening the application scenarios of laser machining.