Search

Due to simplicity, K-means has become a widely used clustering method. However, its clustering result is seriously affected by the initial centers and the allocation strategy makes it hard to identify manifold clusters. Many improved K-means are proposed to accelerate it and improve the quality of initialize cluster centers, but few researchers pay attention to the shortcoming of K-means in discovering arbitrary-shaped clusters. Using graph distance (GD) to measure the dissimilarity between objects is a good way to solve this problem, but computing the GD is time-consuming. Inspired by the idea that granular ball uses a ball to represent the local data, we select representatives from a local neighborhood, called natural density peaks (NDPs). On the basis of NDPs, we propose a novel K-means algorithm for identifying arbitrary-shaped clusters, called NDP-Kmeans. It defines neighbor-based distance between NDPs and takes advantage of the neighbor-based distance to compute the GD between NDPs. Afterward, an improved K-means with high-quality initial centers and GD is used to cluster NDPs. Finally, each remaining object is assigned according to its representative. The experimental results show that our algorithms can not only recognize spherical clusters but also manifold clusters. Therefore, NDP-Kmeans has more advantages in detecting arbitrary-shaped clusters than other excellent algorithms.

Context: Computational drug repurposing methods have been continuously developed in recent years to alleviate the high costs associated with drug development. As drug targets or the products of disease-related genes, proteins play an important role in drug repurposing. Although the potential has been demonstrated, heterogeneous graphs with proteins as independent nodes have yet to be studied, where extracting high-quality protein features from heterogeneous graphs poses a significant challenge. A novel drug repurposing model based on the feature construction of multi-layer ensemble (DRML-Ensemble) is proposed in this study. The performance of DRML-Ensemble, as evaluated on publicly available datasets, achieves an AUPR value of 0.93 and an AUROC value of 0.92, surpassing those of existing state-of-the-art methods. Additionally, DRML-Ensemble demonstrates its notable ability for drug repurposing in Alzheimer's disease., Methods: DRML-Ensemble is primarily composed of multiple layers of heterogeneous graph feature construction (HGFC). Each HGFC can extract protein features by leveraging the relationships between drugs, diseases, and proteins. These protein features are then utilized in subsequent layers to build drug and disease features, facilitating drug repurposing. By stacking multiple layers, optimal protein features can be obtained from the heterogeneous graph, consequently improving the accuracy of drug repurposing. However, an excessive· stacking of layers usually affect the model's training process, for example, causing problems such as overfitting; a multi-layer ensemble prediction module is designed to further improve the model's performance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Plant-sucking insects have intricate associations with a diverse array of microorganisms to facilitate their adaptation to specific ecological niches. The midgut of phytophagous true bugs is generally structured into four distinct compartments to accommodate their microbiota. Nevertheless, there is limited understanding regarding the origins of these gut microbiomes, the mechanisms behind microbial community assembly, and the interactions between gut microbiomes and their insect hosts. In this study, we conducted a comprehensive survey of microbial communities within the midgut compartments of a bean bug Riptortus pedestris, soybean plant, and bulk soil across 12 distinct geographical fields in China, utilizing high-throughput sequencing of the 16 S rRNA gene. Our findings illuminated that gut microbiota of the plant-sucking insects predominantly originated from the surrounding soil environment, and plants also play a subordinate role in mediating microbial acquisition for the insects. Furthermore, our investigation suggested that the composition of the insect gut microbiome was probably shaped by host selection and/or microbe-microbe interactions at the gut compartment level, with marginal influence from soil and geographical factors. Additionally, we had unveiled a noteworthy dynamic in the acquisition of core bacterial taxa, particularly Burkholderia, which were initially sourced from the environment and subsequently enriched within the insect midgut compartments. This bacterial enrichment played a significant role in enhancing insect host reproduction. These findings contribute to our evolving understanding of microbiomes within the insect-plant-soil ecosystem, shedding additional light on the intricate interactions between insects and their microbiomes that underpin the ecological significance of microbial partnerships in host adaptation., (© 2024. The Author(s).)

Background: Circadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between PER and CRY polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity., Methods: A total of 221 preterm infants of gestational age <34 weeks were included in this study (160 in the response group and 61 in the non-response group). The propensity score matching method was used to perform a 1:1 matching for all premature infants, and the general characteristics and clinical outcomes of the two groups were compared. The association between polymorphisms of the circadian transcription repressors PER and CRY and caffeine citrate treatment response in infants with apnea of prematurity was analyzed with co-dominant, dominant, recessive, and over-dominant models, as well as analysis of alleles. Generalized multifactor dimensionality reduction (GMDR) analysis was used to analyze the interaction between the PER and CRY genes., Results: After propensity score matching, 45 preterm infants were included in each of the response and non-response groups, and there were no statistically significant differences in general characteristics between the two groups ( P  > 0.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) ( P  = 0.043), retinopathy of prematurity (ROP) ( P  = 0.035), and invasive ventilation ( P  = 0.027), and their duration of oxygen use ( P  = 0.041) was longer. When corrected for false discovery rate, the PER3 rs228669 recessive model ( P FDR   = 0.045) and the over-dominant model ( P FDR  = 0.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR = 0.28, 95% CI = 0.12-0.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR = 4.18, 95% CI = 1.64-10.66). GMDR analysis revealed an interaction between the PER and CRY genes ( P  < 0.05)., Conclusions: Circadian rhythms may play a role in the response of premature infants to caffeine citrate, and polymorphisms of the PER and CRY genes may influence the effectiveness of caffeine citrate treatment for apnea of prematurity., 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 Xie, Zhuang, Zhu, Zheng, Huang, Ma and Lin.)

The Mammalian orthoreovirus (MRV) infects various mammals, including humans, and is linked to gastrointestinal, respiratory, and neurological diseases. A recent outbreak in Liuzhou, Guangxi, China, led to the isolation of a new MRV strain, GXLZ2301, from fecal samples. This strain replicates in multiple cell lines and forms lattice-like structures. Infected cells exhibit single-cell death and syncytia formation. The virus's titers peaked at 10 7.2 TCID 50 /0.1 mL in PK-15 and BHK cells, with the lowest at 10 3.88 TCID50/0.1 mL in A549 cells. Electron microscopy showed no envelope with a diameter of about 70 nm. Genetic analysis revealed GXLZ2301 as a recombinant strain with gene segments from humans, cows, and pigs, similar to type 3 MRV strains from Italy (2015-2016). Pathogenicity tests indicated that while the bovine MRV strain did not cause clinical symptoms in mice, it caused significant damage to the gut, lungs, liver, kidneys, and brain. The emergence of this MRV strain may pose a threat to the health of animals and humans, and it is recommended that its epidemiology and recombination be closely monitored., 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 Luo, Wang, Tang, Wang, Liu, Wang, Xie, Wang, Ouyang, Chen, Wei, Qin, Pan and Huang.)

Background: Nutritional risk index (NRI) and carcinoembryonic antigen (CEA) are useful prognostic markers in colorectal cancer (CRC); however, the prognostic value of a combination of the NRI and CEA, namely, the NRI and CEA score (NCS), needs further investigation., Methods: Stage I-III CRC patients were collected and then divided into three subgroups by counting the NCS: NCS 1: high NRI with normal CEA; NCS 2: high NRI with elevated CEA or low NRI with normal CEA; and NCS 3: low NRI with elevated CEA. The differences in outcome, counted as disease-free survival (DFS) and overall survival (OS), were tested among the subgroups., Results: A total of 285 patients were enrolled, with 108 in NCS 1, 118 in NCS 2 and 59 in NCS 3. Patient features, including age, tumour deposit, T stage, N stage and TNM stage, were significantly different in the NCS subgroups. Both the DFS (log-rank = 26.06, P<0.001) and OS (log-rank = 39.10, P<0.001) were significant in different NCS subgroups, even in maximum tumour diameter ≤4 cm cases (DFS: log-rank = 21.42, P<0.001; OS: log-rank = 30.95, P<0.001), and NCS 1 patients displayed the best outcome compared with the rest of the subgroups. NCS was also found to be an independent risk factor for both DFS and OS., Conclusions: NCS was a useful prognostic indicator in stages I-III CRC patients., (© 2024 Royal Australasian College of Surgeons.)

Alterations in steroid hormone regulation have been implicated in the etiology and progression of autism spectrum disorders (ASD), with the enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1)-a key catalyst in cholesterol side-chain cleavage, prominently expressed in the adrenal glands, ovaries, testes, and placenta-standing at the forefront of these investigations. The potential link between aberrations in placental Cyp11a1 expression and the resultant neurodevelopmental disorders, along with the mechanisms underpinning such associations, remains inadequately delineated. In this study, we employed a placental trophoblast-specific Cyp11a1 Hipp11 (H11) knock-in murine model to dissect the phenotypic manifestations within the placenta and progeny, thereby elucidating the underlying mechanistic pathways. Behavioral analyses revealed a diminution in social interaction capabilities alongside an augmented anxiety phenotype, as evidenced by open field and elevated plus maze assessments; both phenotypes were ameliorated after vitamin D3 supplementation. Electrophysiological assays underscored the augmented inhibition of paired-pulse facilitation, indicating impaired neuroplasticity in Cyp11a1 H11-modified mice. An elevation in progesterone concentrations was noted, alongside a significant upregulation of Th1-related cytokines (IL-6 and TNFα) across the plasma, placental, and frontal cortex-a pathological state mitigable through vitamin D3 intervention. Western blotting revealed a vitamin D-mediated rectification of vitamin D receptor and PGC-1α expression dysregulations. Immunofluorescence assays revealed microglial activation in the knock-in model, which was reversible upon vitamin D3 treatment. In conclusion, Cyp11a1 overexpression in the placenta recapitulated an autism-like phenotype in murine models, and vitamin D3 administration effectively ameliorated the resultant neurobehavioral and neuroinflammatory derangements. This study substantiates the application of Cyp11a1 as a biomarker in prenatal diagnostics and posits that prenatal vitamin D3 supplementation is a viable prophylactic measure against perturbations in steroid hormone metabolism associated with ASD pathogenesis., 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.)

Drug repurposing is an effective method to reduce the time and cost of drug development. Computational drug repurposing can quickly screen out the most likely associations from large biological databases to achieve effective drug repurposing. However, building a comprehensive model that integrates drugs, proteins, and diseases for drug repurposing remains challenging. This study proposes a drug repurposing method based on the ternary heterogeneous graph attention network (DRTerHGAT). DRTerHGAT designs a novel protein feature extraction process consisting of a large-scale protein language model and a multi-task autoencoder, so that protein features can be extracted accurately and efficiently from amino acid sequences. The ternary heterogeneous graph of drug-protein-disease comprehensively considering the relationships among the three types of nodes, including three homogeneous and three heterogeneous relationships. Based on the graph and the extracted protein features, the deep features of the drugs and the diseases are extracted by graph convolutional networks (GCN) and heterogeneous graph node attention networks (HGNA). In the experiments, DRTerHGAT is proven superior to existing advanced methods and DRTerHGAT variants. DRTerHGAT's powerful ability for drug repurposing is also demonstrated in Alzheimer's disease., 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.)

Accurately predicting drug-target interactions is a critical yet challenging task in drug discovery. Traditionally, pocket detection and drug-target affinity prediction have been treated as separate aspects of drug-target interaction, with few methods combining these tasks within a unified deep learning system to accelerate drug development. In this study, we propose EMPDTA, an end-to-end framework that integrates protein pocket prediction and drug-target affinity prediction to provide a comprehensive understanding of drug-target interactions. The EMPDTA framework consists of three main modules: pocket online detection, multimodal representation learning for affinity prediction, and multi-task joint training. The performance and potential of the proposed framework have been validated across diverse benchmark datasets, achieving robust results in both tasks. Furthermore, the visualization results of the predicted pockets demonstrate accurate pocket detection, confirming the effectiveness of our framework.

Although our knowledge of autism spectrum disorder (ASD) has been deepened, the accurate diagnosis of ASD from normal individuals is still left behind. In this study, we proposed to apply the spatial pattern of the network topology (SPN) to identify children with ASD from normal ones. Based on two independent batches of electroencephalogram datasets collected separately, the accurate recognition of ASD from normal children was achieved by applying the proposed SPN features. Since decreased long-range connectivity was identified for children with ASD, the SPN features extracted from the distinctive topological architecture between two groups in the first dataset were used to validate the capacity of SPN in classifying ASD, and the SPN features achieved the highest accuracy of 92.31%, which outperformed the other features e.g., power spectrum density (84.62%), network properties (76.92%), and sample entropy (73.08%). Moreover, within the second dataset, by using the model trained in the first dataset, the SPN also acquired the highest sensitivity in recognizing ASD, when compared to the other features. These results consistently illustrated that the functional brain network, especially the intrinsic spatial network topology, might be the potential biomarker for the diagnosis of ASD., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Sleep apnea-specific hypoxic burden (SASHB) is a polysomnographic metric that comprehensively measures the degree of nocturnal desaturation caused by obstructive sleep apnea. This research was conducted to elucidate the relationship between SASHB and coronary artery disease (CAD) severity., Methods: We carried out a prospective study of hospitalized patients with CAD of unstable angina who were expected to undergo invasive coronary angiography at Beijing Anzhen Hospital from February to September 2023. SASHB values were calculated using a self-programmed C +  + program. Multivariable logistic regression analysis was applied to identify the association between SASHB and the prevalence of severe CAD, documented by the Gensini Score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) Score., Results: This study enrolled 137 patients with a median age of 59 years, 96 (70.1%) of whom were male. A total of 125 (91.2%) patients had coronary stenosis of ≥ 50% in at least one location. Patients with a high SASHB of ≥ 18% min/h had a significantly higher Gensini Score (32.0 vs. 18.5, P = 0.002) and SYNTAX Score (14.0 vs. 7.0, P = 0.002) than those with a low SASHB. After adjusting for multiple covariates, a high SASHB was significantly associated with the prevalence of severe CAD, determined by a Gensini Score ≥ 21 (OR 2.67, P = 0.008) or a SYNTAX Score > 22 (OR 4.03, P = 0.016)., Conclusion: Our findings revealed a robust and independent association between SASHB and CAD severity in patients with unstable angina, highlighting the potential value of SASHB as a predictor of risk and a target for interventions aimed at preventing cardiovascular diseases., Trial Registration: Chinese Clinical Trial Registry No. ChiCTR2300067991 on February 2, 2023., (© 2024. The Author(s).)

In the real world, data distributions often exhibit multiple granularities. However, the majority of existing neighbor-based machine-learning methods rely on manually setting a single-granularity for neighbor relationships. These methods typically handle each data point using a single-granularity approach, which severely affects their accuracy and efficiency. This paper adopts a dual-pronged approach: it constructs a multi-granularity representation of the data using the granular-ball computing model, thereby boosting the algorithm's time efficiency. It leverages the multi-granularity representation of the data to create tailored, multi-granularity neighborhood relationships for different task scenarios, resulting in improved algorithmic accuracy. The experimental results convincingly demonstrate that the proposed multi-granularity neighbor relationship effectively enhances KNN classification and clustering methods. The source code has been publicly released and is now accessible on GitHub at https://github.com/xjnine/MGNR.

Background: The study aimed to establish a link between blood ethylene oxide (EO) levels and periodontitis, given the growing concern about EO's detrimental health effects., Materials and Methods: The study included 1006 adults from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) dataset. We assessed periodontitis prevalence across groups, used weighted binary logistic regression and restricted cubic spline fitting for HbEO-periodontitis association, and employed Receiver Operating Characteristic (ROC) curves for prediction., Results: In the periodontitis group, HbEO levels were significantly higher (40.57 vs. 28.87 pmol/g Hb, P < 0.001). The highest HbEO quartile showed increased periodontitis risk (OR = 2.88, 95% CI: 1.31, 6.31, P = 0.01). A "J"-shaped nonlinear HbEO-periodontitis relationship existed (NL-P value = 0.0116), with an inflection point at ln-HbEO = 2.96 (EO = 19.30 pmol/g Hb). Beyond this, ln-HbEO correlated with higher periodontitis risk. A predictive model incorporating sex, age, education, poverty income ratio, alcohol consumption, and HbEO had 69.9% sensitivity and 69.2% specificity. The model achieved an area under the ROC curve of 0.761., Conclusions: These findings suggest a correlation between HbEO levels and an increased susceptibility to periodontitis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction and Aims: Periodontitis, a chronic inflammatory condition affecting the supporting structures of the teeth, is a substantial public health burrden whilst impacting the life quality of those affected. Elevated levels of systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) have been implicated in various inflammatory conditions. This study aimed to investigate the relationship between SII and SIRI with periodontitis., Methods: The study examined a total of 8666 participants in the 2009 to 2014 National Health and Nutrition Examination Survey (NHANES). The study compared the weighted prevalence of periodontitis among various groups. The association between SII, SIRI levels, and periodontitis was analyzed using binary logistic regression. Additionally, we explored nonlinear relationships between SII, SIRI, and the prevalence of periodontitis using restricted cubic spline (RCS) plots., Results: Among participants in the fourth quartile (Q4) of SII and SIRI, the highest prevalence of periodontitis was observed, with rates of 44.87% and 48.41%, respectively. After adjusting for all covariates, the odds ratio (OR) for periodontitis associated with SII Q4 was 1.19 (95% CI 1.02, 1.39, P = .03), while for SIRI Q4, it was 1.18 (95% CI 1.01, 1.39, P = .04). In addition, the results of sensitivity analysis revealed consistent findings, indicating that after adjusting for all covariates, the OR for periodontitis associated with SII Q4 and SIRI Q4 remained statistically significant. Specifically, the OR for periodontitis associated with SII Q4 was 1.19 (95% CI 1.02, 1.39, P = .03), while for SIRI Q4, it was 1.19 (95% CI 1.01, 1.40, P = .04)., Conclusions: These results indicate that elevated SII and SIRI levels are associated with an increased prevalence of periodontitis., Clinical Relevance: These findings suggest a potential connection between systemic inflammation and periodontitis, highlighting the importance of periodontitis patients being aware of their systemic diseases that are inflammatory in nature such as chronic cardiovascular afflictions., Competing Interests: Conflict of 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. Published by Elsevier Inc.)

There is increasing evidence that alterations in gut microbiota (GM) composition are associated with autism spectrum disorder (ASD), but no reliable causal relationship has been established. Therefore, a 2-sample Mendelian randomization (MR) study was conducted to reveal a potential causal relationship between GM and ASD. Instrumental variables for 211 GM taxa were obtained from genome-wide association studies (GWAS) and Mendelian randomization studies to estimate their impact on ASD risk in the iPSYCH-PGC GWAS dataset (18,382 ASD cases and 27,969 controls). Inverse variance weighted (IVW) is the primary method for causality analysis, and several sensitivity analyses validate MR results. Among 211 GM taxa, IVW results confirmed that Tenericutes (P value = .0369), Mollicutes (P value = .0369), Negativicutes (P value = .0374), Bifidobacteriales (P value = .0389), Selenomonadales (P value = .0374), Bifidobacteriaceae (P value = .0389), Family XIII (P value = .0149), Prevotella7 (P value = .0215), Ruminococcaceae NK4A214 group (P value = .0205) were potential protective factors for ASD. Eisenbergiella (P value = .0159) was a possible risk factor for ASD. No evidence of heterogeneous, pleiotropic, or outlier single-nucleotide polymorphism was detected. Additionally, further sensitivity analysis verified the robustness of the above results. We confirm a potential causal relationship between certain gut microbes and ASD, providing new insights into how gut microbes mediate ASD. The association between them needs to be further explored and will provide new ideas for the prevention and treatment of ASD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This systematic review and meta-analysis aimed to evaluate the relationship between the prognostic nutritional index (PNI) and intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Kawasaki disease (KD)., Methods: The relevant literature was searched on PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar up to August 5, 2023. A pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were calculated to assess the predicted values of PNI in KD patients with IVIG resistance and CAL., Results: A total of 8 articles containing 10 studies involving 7,047 participants were included. The pooled results revealed a pooled sensitivity of 0.44 (0.25-0.65), a pooled specificity of 0.87 (0.73-0.94), a pooled PLR of 3.4 (2.0-5.9), a pooled NLR of 0.65 (0.48-0.87), a pooled DOR of 5.26 (2.76-10.02), and a pooled AUC of 0.75 (0.71-0.78) in the diagnosis of KD with CAL. The pooled results suggested that a pooled sensitivity was 0.69 (0.60-0.77), specificity was 0.76 (0.69-0.82), PLR was 2.9 (2.1-4.1), NLR was 0.40 (0.29-0.56), DOR was 7.27 (3.89-13.59), and AUC was 0.79 (0.75-0.82) in the diagnosis of KD with IVIG resistance. The combined results revealed the pooled sensitivity was 0.63 (0.58-0.67), specificity was 0.82 (0.80-0.83), PLR was 3.09 (1.06-8.98), NLR was 0.38 (0.07-2.02), DOR was 8.23 (0.81-83.16) in differentiating KD from febrile patients. These findings demonstrated low sensitivity and relatively high specificity of PNI for KD, KD-CAL, and IVIG-resistant KD., Conclusion: In conclusion, this study was the first systematic review and meta-analysis of the diagnostic value of PNI in KD with IVIG resistance and CAL. The results suggested that PNI could be used as biomarkers for distinguish KD, KD with CAL, and KD with IVIG resistance., 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 Zhong, Xie, Wang, Chen, Yang and Xie.)

The interaction of multiple drugs could lead to severe events, which cause medical injuries and expenses. Accurate prediction of drug-drug interaction (DDI) events can help clinicians make effective decisions and establish appropriate therapy programs. However, there exist two issues worthy of further consideration. (i) The global features of drug molecules should be paid attention to, rather than just their local characteristics. (ii) The fusion of multi-source features should also be studied to capture the comprehensive features of the drug. This study designs a Multi-Source Feature Fusion framework with Multiple Attention blocks named MSFF-MA-DDI that utilizes multimodal data for DDI event prediction. MSFF-MA-DDI can (i) encode global correlations between long-distance atoms in drug molecular sequences by a self-attention layer based on a position embedding block and (ii) fuse drug sequence features and heterogeneous features (chemical substructure, target, and enzyme) through a multi-head attention block to better represent the features of drugs. Experiments on real-world datasets show that MSFF-MA-DDI can achieve performance that is close to or even better than state-of-the-art models. Especially in cold start scenarios, the model can achieve the best performance. The effectiveness of the model is also supported by the case study on nervous system drugs. The source codes and data are available at https://github.com/BioCenter-SHU/MSFF-MA-DDI., 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 © 2023 Elsevier Ltd. All rights reserved.)

Two novel naturally occurring [4 + 2] Diels-Alder cycloaddition ergosteroids (1 and 2), three undescribed oxidized ergosteroids (3-5), and eleven known analogs (6-16) were isolated from Penicillium herquei. Compounds 1 and 2 represent the first reported cycloadducts of a steroid with 1,4,6-trimethyl-1,6-dihydropyridine-2,5-dione or 4,6-dimethyl-1,6-dihydropyridine-2,5-dione to date. Compound 3 is the C-15 epimer of (22E,24R)-9α,11β-dihydroxyergosta-4,6,8(14),22-tetraen-3-one (14). The chemical structures of these compounds were elucidated through widespread spectroscopic analyses, mainly including HRESIMS and 1D and 2D NMR data, calculated 13 C NMR-DP4+ analysis, and electronic circular dichroism (ECD) data analyses. Biological evaluations of Compounds 1-16 revealed that 3, 9-11, and 15 inhibited the production of NO in LPS-induced RAW264.7 cells with an IC 50 value from 7.37 ± 0.69 to 38.9 ± 2.25 μM (the positive control dexamethasone IC 50 : 9.54 ± 0.71 μM). In addition, Compound 3 exhibited a potent inhibitory effect on the secretion of the proinflammatory cytokines TNF-α and IL-6, the transcription level of the proinflammatory macrophage markers TNF-α, and the expression of the iNOS protein., 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 © 2023. Published by Elsevier Inc.)

Osteosarcoma (OS) is the most common malignancy in children and adolescents and has a high probability of recurrence and metastasis. A growing number of studies have shown that neutrophil extracellular traps (NETs) are strongly associated with cancer metastasis, but in osteosarcoma, genes associated with NETs that promote osteosarcoma recurrence and metastasis remain to be explored. We systematically investigated the gene expression patterns of NETs in OS samples from the GEO database. NETs molecular typing was evaluated based on NETs expression profiles, and the association between NETs molecular subtypes and immune microenvironment and metastatic features were explored. Ultimately, we constructed a signature model and column line graph associated with metastasis prediction and screened possible potential drugs for metastatic osteosarcoma. We established two different molecular subtypes of NETs, which showed significant differences in metastatic status, metastasis time, tumor immune microenvironment, and biological effects. We also constructed a NETs-related gene metastasis signature(NRGMS) to assess the expression pattern of NETs in patients to predict metastatic recurrence in osteosarcoma patients. We screened for TOMM40 and FH associated with metastatic recurrence in osteosarcoma patients. Overall, this study constructs a predictive model for osteosarcoma metastasis of NETs-related genes, which is expected to provide new insights into the metastasis of osteosarcoma., (© 2024. The Author(s).)

Ubiquitin-specific proteases (USPs), as one of the deubiquitinating enzymes (DUBs) families, regulate the fate of proteins and signaling pathway transduction by removing ubiquitin chains from the target proteins. USPs are essential for the modulation of a variety of physiological processes, such as DNA repair, cell metabolism and differentiation, epigenetic modulations as well as protein stability. Recently, extensive research has demonstrated that USPs exert a significant impact on innate and adaptive immune reactions, metabolic syndromes, inflammatory disorders, and infection via post-translational modification processes. This review summarizes the important roles of the USPs in the onset and progression of inflammatory diseases, including periodontitis, pneumonia, atherosclerosis, inflammatory bowel disease, sepsis, hepatitis, diabetes, and obesity. Moreover, we highlight a comprehensive overview of the pathogenesis of USPs in these inflammatory diseases as well as post-translational modifications in the inflammatory responses and pave the way for future prospect of targeted therapies in these inflammatory diseases., 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 Chen, Zhang, Li, Li, Xie, Weng, Tan, Liu, Guo and Wang.)

A surgical site infection (SSI) is one of the most common complications of spinal surgery. Malnutrition has also been linked to SSI after other surgical procedures. However, whether malnutrition is a risk factor for SSI after spinal surgery remains controversial. Therefore, we performed a meta-analysis to comprehensively evaluate the relationship between malnutrition and SSI. Relevant studies of the correlation between malnutrition and SSI were retrieved from the Cochrane Library, EMBASE, PubMed, Web of Science, China National Knowledge Infrastructure and Wanfang Data from database inception to 21 May 2023. Two reviewers independently assessed the included studies, and a meta-analysis was performed using STATA 17.0 software. A total of 24 articles with 179 388 patients were included: 3919 and 175 469 cases comprised the SSI and control groups, respectively. The meta-analysis results showed that malnutrition significantly increased the SSI incidence (odds ratio, 1.811; 95% confidence interval, 1.512-2.111; p < 0.001). These results suggest that patients with malnutrition are at higher risk for SSI after surgery. However, because of significant differences in sample sizes among studies, and because some studies had limitations to their methodological quality, further validation of these results by additional high-quality studies with larger sample sizes is necessary., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate the effects of soybean, medium-chain triacylglycerols (MCTs), olive oil, and fish oil (SMOF) on short-term clinical outcomes, physical growth, and extrauterine growth retardation (EUGR) in very preterm infants., Methods: This was a multicenter retrospective cohort study of very preterm infants hospitalized in neonatal intensive care units at five tertiary hospitals in China between January 2021 and December 2021. According to the type of fat emulsion used in parenteral nutrition (PN), eligible very preterm infants were divided into the MCTs/long-chain triacylglycerol (MCT/LCT) group and SMOF group. Change in weight z-score (weight Δz) between measurements at birth and at 36 wk of postmenstrual age or at discharge, the incidence of EUGR, and short-term clinical outcomes between the two groups were compared and analyzed., Results: We enrolled 409 very preterm infants, including 205 in the MCT/LCT group and 204 in the SMOF group. Univariate analysis showed that infants in the SMOF group had significantly longer duration of invasive mechanical ventilation and PN, longer days to reach total enteral nutrition, and a higher proportion of maximum weight loss than those in MCT/LCT group (all P < 0.05). After adjusting for the confounding variables, multifactorial logistic regression analysis of short-term clinical outcomes showed that SMOF had protective effects on PN-associated cholestasis (odds ratio [OR], 0.470; 95% confidence interval [CI], 0.266-0.831) and metabolic bone disease of prematurity (OR, 0.263; 95% CI, 0.078-0.880). Additionally, SMOF was an independent risk factor for lower weight growth velocity (β = -0.733; 95% CI, -1.452 to -0.015) but had no effect on the incidence of EUGR (OR, 1.567; 95% CI, 0.912 to -2.693)., Conclusion: Compared with MCT/LCT, SMOF can reduce the risk for PN-associated cholestasis and metabolic bone disease of prematurity in very preterm infants and has a negative effect on growth velocity but has no effect on the incidence of EUGR., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Three new hetisine type C 20 -diterpenoid alkaloids, named as trichophorines A-C ( 1-3 ), were isolated from Delphinium trichophorum , together with nine known alkaloids ( 4-12 ). Their structures were elucidated on the basis of spectroscopic data (1D, 2D NMR, single-crystal X-ray, and HR-ESI-MS). All compounds were evaluated for the inhibitory activities against LPS induced NO production in RAW 264.7 macrophage cells, and none of them showed considerable inhibitory activity.

Carbon fiber-reinforced epoxy resin composites have poor high temperature resistance and are prone to thermal damage during service in the aerospace field. The purpose of this study was to evaluate the thermal decomposition (pyrolysis) characteristics of carbon fiber-reinforced epoxy composites and reasonably predict their thermal decomposition under arbitrary temperature conditions. The kinetic analysis was conducted on the thermal decomposition of carbon fiber-reinforced epoxy resin composites (USN15000/9A16/RC33, supplied by Weihai GuangWei Composites Co., Ltd. Weihai City, Shandong Province, China) under a nitrogen environment, and an improved model of pyrolysis prediction suitable for the arbitrary temperature program was developed in this work. The results showed that the carbon fiber-reinforced epoxy composites begin to degrade at about 500 K, and the peak value of the weight loss rate at the respective heating rate appears in the range of 650 K to 750 K. A single-step reaction can characterize the thermal decomposition of carbon fiber-reinforced epoxy composites in a nitrogen atmosphere, and a wide variety of isoconversional approaches can be used for the calculation of the kinetic parameters. The proposed model of pyrolysis prediction can avoid numerous limitations of temperature integration, and it shows good prediction accuracy by reducing the temperature rise between sampling points. This study provides a reference for the kinetic analysis and pyrolysis prediction of carbon fiber-reinforced epoxy composites.

Background: In recent years, many studies have focused on the relationship between noncoding RNAs (ncRNAs) and Kawasaki disease (KD). Studies have indicated that ncRNAs are associated with the occurrence and development of KD. Thus, we performed a systematic review and meta-analysis to investigate the diagnostic value of ncRNAs in KD patients., Methods: We searched the PubMed, Web of Science, Embase and Cochrane Library, China National Knowledge Infrastructure, VIP, China Biology Medicine disc databases, and Wanfang databases until August 25, 2023 and screened all eligible studies focusing on the diagnostic performance of ncRNAs in KD patients., Results: In total, 535 articles were found, and 28 articles were included in this systematic review and meta-analysis. The calculated area under the curve value was 0.880 (95% confidence intervals, 0.840-0.900). The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.790, 0.830, 4.610, and 0.260, respectively. The pooled diagnostic odds ratio was 17.890 (95% confidence intervals, 13.110-24.420), indicating a relatively good diagnostic performance of the ncRNAs for detecting KD. In addition, the diagnostic value of micro RNAs in KD was better than that of long noncoding RNAs and circular noncoding RNAs. A subgroup analysis by specimen indicated a better diagnostic value of ncRNAs in plasma and platelet than serum. The diagnostic accuracy of ncRNAs was better in febrile controls than in healthy control groups, indicating a relatively good accuracy in distinguishing KD patients from febrile diseases., Conclusions: This systematic review and meta-analysis demonstrated that ncRNAs could be used as novel biomarkers for detecting KD. More studies should be conducted in the future to verify the diagnostic values of ncRNAs in KD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: The study aimed to provide evidence of the relationship between probiotics consumption and periodontitis., Materials and Methods: A total of 4577 adults who participated in the National Health and Nutrition Examination Survey (NHANES) during 2009-2014 were included in the study. The weighted prevalence of periodontitis was compared among different groups, and a weighted binary logistic regression analysis was conducted to explore the relationship between probiotic consumption and periodontitis. Receiver operating characteristic (ROC) curves were used to assess the role of probiotic consumption in the periodontitis prediction model., Results: Participants who consumed probiotics had a significantly lower prevalence of periodontitis than those who did not (41.08% vs. 27.83%, p < .001). After fully adjusting for all factors, the odds ratio associated with periodontitis for consuming probiotics was 0.70 (95% confidence interval 0.54-0.92, p = .01) when compared with those who did not consume probiotics. A predictive model including age, sex, ethnicity, poverty income ratio, smoking status and probiotics had 77.0% sensitivity and 60.3% specificity in detecting periodontitis in US adults and achieved an area under the ROC curve of 0.749., Conclusions: These results indicate that consuming probiotics is associated with a reduced risk of periodontitis., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Seventeen compounds were isolated and identified from the ethyl acetate part of Zanthoxylum bungeanum Maxim., including one new compound 18-acetyloxyneocryptotanshinone ( 1 ) and 16 known compounds ( 2-17 ). Their structures were elucidated by extensive spectroscopy. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD). All compounds were evaluated for the inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, of which 1 and 10 exhibited the most significant inhibitory effect, with IC 50 of 17.29 and 10.27  μ M, respectively.

Phishing attacks are evolving with more sophisticated techniques, posing significant threats. Considering the potential of machine-learning-based approaches, our research presents a similar modern approach for web phishing detection by applying powerful machine learning algorithms. An efficient layered classification model is proposed to detect websites based on their URL structure, text, and image features. Previously, similar studies have used machine learning techniques for URL features with a limited dataset. In our research, we have used a large dataset of 20,000 website URLs, and 22 salient features from each URL are extracted to prepare a comprehensive dataset. Along with this, another dataset containing website text is also prepared for NLP-based text evaluation. It is seen that many phishing websites contain text as images, and to handle this, the text from images is extracted to classify it as spam or legitimate. The experimental evaluation demonstrated efficient and accurate phishing detection. Our layered classification model uses support vector machine (SVM), XGBoost, random forest, multilayer perceptron, linear regression, decision tree, naïve Bayes, and SVC algorithms. The performance evaluation revealed that the XGBoost algorithm outperformed other applied models with maximum accuracy and precision of 94% in the training phase and 91% in the testing phase. Multilayer perceptron also worked well with an accuracy of 91% in the testing phase. The accuracy results for random forest and decision tree were 91% and 90%, respectively. Logistic regression and SVM algorithms were used in the text-based classification, and the accuracy was found to be 87% and 88%, respectively. With these precision values, the models classified phishing and legitimate websites very well, based on URL, text, and image features. This research contributes to early detection of sophisticated phishing attacks, enhancing internet user security.

For Chinese sucker (Myxocyprinus asiaticus), passing through a dam with fast flow and cold water are always unavoidable, and this process can cause stress, disease or even death. In this study, comparative transcriptome analysis was conducted to investigate the potential immune mechanism in head kidney of M. asiaticus with swimming fatigue stress and cold stress after fatigue. In general, a total of 181,781 unigenes were generated, and 38,545 differentially expressed genes (DEGs) were identified. In these DEGs, 22,593, 7286 and 8666 DEGs were identified among groups of fatigue vs. cold, control vs. cold, and control vs. fatigue, respectively. Enrichment analysis revealed these DEGs were involved in coagulation cascades and complement, natural killer cell mediated cytotoxicity, antigen processing and presentation, Toll-like receptor signaling pathways, and chemokine signaling pathway. Notably, immune genes including heat shock protein 4a (HSP4a), HSP70 and HSP90α genes were significantly up-regulated in fishes with cold stress after fatigue. Differently, more immune genes in control vs. cold compared with that in control vs. fatigue were significantly down-regulated expression, such as claudin-15-like, Toll-like receptor 13, antimicrobial peptide (hepcidin), immunoglobulin, CXCR4 chemokine receptor, T-cell receptor, complement factor B/C2-A3, and interleukin 8. In this study, the number of DEGs in the head kidney was less than that our previous study in the spleen, which we speculated was more sensitive to changes in water temperature than the head kidney. In summary, lots of immune-related genes in the head kidney were down-regulated under cold stress after fatigue, suggesting that M. asiaticus might have experienced severe immunosuppression in the process of passing through the dam., 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 © 2023. Published by Elsevier Inc.)

Loss of Smad3 and the consequent activation of myocardin-related transcription factor (MRTF) are associated with vascular pathologies. This study aimed to examine the impact of persistent hypoxia with intermittent aggravation (PI hypoxia) on cellular senescence and pulmonary arterial remodeling mediated by the Smad3/MRTF imbalance. We examined the effects of PI hypoxia on the Smad3/MRTF pathway and cellular senescence using human pulmonary artery endothelial cells (HPAECs) and in vivo studies in rats. The senescent degree was evaluated using β-galactosidase staining, p16 quantitation and the measurement of senescence-associated secretory phenotype. Structural data in the pathological analysis of pulmonary artery remodeling were collected. Compared to the control, HPAECs and pulmonary tissue from rats exposed to PI hypoxia showed a significantly higher senescent degree, lower expression of Smad3, and higher MRTF levels. The overexpression of Smad3 significantly mitigated HPAECs senescence in vitro. Further, treatment with CCG-203971, which inhibits MRTF, increased Smad3 levels and reduced β-galactosidase positive cells in rat lung tissue. This intervention also alleviated PI hypoxia-induced pathological changes, including remodeling indices of pulmonary arterial thickening, muscularization, and collagen formation. In conclusion, imbalanced Smad3/MRTF signaling is linked to PI hypoxia-induced senescence and pulmonary arterial remodeling, making it a potential therapeutic target for patients with sleep apnea and chronic obstructive pulmonary disease.

Background: To explore the factors associated with prolonged enhanced recovery after surgery (ERAS) time in gastric cancer patients who underwent gastrectomy., Methods: This was a retrospective of patients with gastric cancer who received ERAS at our hospital between 01/2014 and 01/2022. The outcome was prolonged ERAS time. Factors associated with prolonged ERAS time of patients undergoing gastric cancer surgery were analyzed by logistic regression., Results: Among 663 patients, 182 (27.6%) patients had a prolonged ERAS time. The postoperative time to the first flatus time was 2.8 ± 1.2 days. There were 41 (6.2%) patients with intestinal obstruction, 25 (3.8%) with abdominal infection, and four (0.5%) with anastomotic leakage. The multivariable analysis showed that age >80 years (OR = 1.57, 95% CI: 1.31-4.40, P = 0.048), laparoscopic surgery (OR = 0.45, 95% CI: 0.21-0.95, P = 0.035), intraoperative jejunostomy (OR = 334.60, 95% CI: 2.81-39,831.90, P = 0.017), postoperative time to the first flatus time (OR = 3.79, 95% CI: 1.23-11.68, P = 0.021), total gastrectomy (OR = 0.08, 95% CI: 0.01-0.94, P = 0.044), and patient compliance with ERAS (OR = 0.01, 95% CI: 0-0.09, P < 0.001) were independently associated with prolonged ERAS time., Conclusions: Age >80 years, laparoscopic surgery, intraoperative jejunostomy, postoperative time to the first flatus time, total gastrectomy, and patient compliance with ERAS might be factors associated with prolonged ERAS time in gastric cancer patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A chemical investigation of the EtOAc extract of the endophytic fungus Penicillium herquei led to the isolation of nine undescribed oxidized ergosterols, penicisterols A-I (1-9), along with ten known analogs (10-19). Their structures and absolute configurations were elucidated by a combination of spectroscopic data analysis, quantum-chemical electronic circular dichroism (ECD) calculations and comparisons, [Rh 2 (OCOCF 3 ) 4 ]-induced ECD experiments, DFT-calculated 13 C chemical shifts and DP4+ probability analysis. Compound 1 was a rare example of ergosterol in which the bond between C-8 and C-9 was cleaved to form an enol ether. Moreover, compound 2 possessed a rare (2,5-dioxo-4-imidazolidinyl)-carbamic acid ester group substituted at C-3. All undescribed oxidized ergosterols (1-9) were evaluated for their cytotoxic activity against five cancer cell lines including 4T1 (mouse breast carcinoma), A549 (human pulmonary carcinoma), HCT-116 (human colorectal carcinoma), HeLa (human cervical carcinoma) and Hepg2 (human hepatoma carcinoma) cells. Compounds 2 and 3 displayed moderate cytotoxic activity against 4T1, A549 and HeLa cells, with IC 50 values ranging from 17.22 to 31.35 μM., 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 © 2023 Elsevier Ltd. All rights reserved.)

Natural holoferritin, containing average 2000 Fe 3+ /ferritin, has been considered as promising iron supplementary in food and medical science. However, the low extraction yields highly limited its practical application. Herein, we provided a facile strategy for holoferritin preparation through in vivo microorganism-directed biosynthesis, and the structure, iron content, and the composition of iron core have been investigated. The results revealed that in vivo biosynthesized holoferritin possesses great monodispersity and water-solubility. In addition, the in vivo biosynthesized holoferritin contains a comparative iron content as compared to natural holoferritin, giving the ratio of ∼ 2500 iron/ferritin. Besides, the composition of iron core has been identified as ferrihydrite and FeOOH, and three steps might be involved in iron core formation. This work highlighted that the microorganism-directed biosynthesis could be an efficient strategy for preparation of holoferritin, which might be beneficial for its practical application for iron supplementation., 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 © 2023 Elsevier Ltd. All rights reserved.)

Four new compounds ( 1 - 4 ) were isolated from the whole plants of two species of Delphinium , including two C 20 -diterpenoid alkaloids, umbrodines A and B ( 1 and 2 ), and a dibenzoxazepinone, umbrolide A ( 3 ) from Delphinium umbrosum Hand.-Mazz. and a C 20 -diterpenoid alkaloid, kingiadine ( 4 ) from Delphinium kingianum Bruhl. ex Huth. Ten known diterpenoid alkaloids were also isolated. Their structures were elucidated via HR-ESIMS, IR, and NMR data. Lycoctonine ( 11 ) and delectinine ( 12 ) exhibited appreciable cardiac activity. Furthermore, 11 and 12 showed cardioprotective effects against doxorubicin-induced toxicity in H9c2 cells, with the maximum protection rates of 61.63% and 51.18%, respectively.

Background and Purpose: The presence of microvascular invasion (MVI) is a crucial indicator of postoperative recurrence in patients with hepatocellular carcinoma (HCC). Detecting MVI before surgery can improve personalized surgical planning and enhance patient survival. However, existing automatic diagnosis methods for MVI have certain limitations. Some methods only analyze information from a single slice and overlook the context of the entire lesion, while others require high computational resources to process the entire tumor with a three-dimension (3D) convolutional neural network (CNN), which could be challenging to train. To address these limitations, this paper proposes a modality-based attention and dual-stream multiple instance learning(MIL) CNN., Materials and Methods: In this retrospective study, 283 patients with histologically confirmed HCC who underwent surgical resection between April 2017 and September 2019 were included. Five magnetic resonance (MR) modalities including T2-weighted, arterial phase, venous phase, delay phase and apparent diffusion coefficient images were used in image acquisition of each patient. Firstly, Each two-dimension (2D) slice of HCC magnetic resonance image (MRI) was converted into an instance embedding. Secondly, modality attention module was designed to emulates the decision-making process of doctors and helped the model to focus on the important MRI sequences. Thirdly, instance embeddings of 3D scans were aggregated into a bag embedding by a dual-stream MIL aggregator, in which the critical slices were given greater consideration. The dataset was split into a training set and a testing set in a 4:1 ratio, and model performance was evaluated using five-fold cross-validation., Results: Using the proposed method, the prediction of MVI achieved an accuracy of 76.43% and an AUC of 74.22%, significantly surpassing the performance of the baseline methods., Conclusion: Our modality-based attention and dual-stream MIL CNN can achieve outstanding results for MVI prediction., 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 Li, Wang, Zhu, Xu, Wei, Xie and Zhang.)

Objective: Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA., Methods: Newly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness ( N  = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality., Results: In cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69-0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05-1.31) and women (OR 1.26, 95% CI 1.10-1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5-8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05-1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality., Conclusion: The implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized., Competing Interests: EO is a member of the Board of Directors of the American Academy of Sleep Medicine. VS serves as a consultant for ResMed, Jazz Pharmaceuticals, Bayer, Lilly, Sleep Number, Zoll, Respicardia, and Huxley. 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 Covassin, Lu, St. Louis, Chahal, Schulte, Mansukhani, Xie, Lipford, Li, Ramar, Caples, Gay, Olson, Silber, Li and Somers.)

Background: Accumulating evidence suggests that alterations in gut microbiota composition and diversity are associated with Atopic dermatitis (AD). But until now, the causal association between them has been unclear., Methods: We employed a two-sample Mendelian Randomization (MR) study to estimate the potential causality of gut microbiota on AD risk. The summary statistics related to the gut microbiota were obtained from a large-scale genome-wide genotype and 16S fecal microbiome dataset from 18,340 individuals (24 cohorts) analyzed by the MiBioGen Consortium, comprising 211 gut microbiota. AD data were also derived from strictly defined AD data collected by FinnGen biobank analysis, which included 218,467 European ancestors (5,321 AD patients and 213,146 controls). The inverse variance weighted method (IVW), weighted median (WME), and MR-Egger were used to determine the changes of AD pathogenic bacterial taxa, followed by sensitivity analysis including horizontal pleiotropy analysis, Cochran's Q test, and the leave-one-out method to assess the reliability of the results. In addition, MR Steiger's test was used to test the suppositional relationship between exposure and outcome., Results: A total of 2,289 SNPs ( p < 1 × 10 -5 ) were included, including 5 taxa and 17 bacterial characteristics (1 phylum, 3 classes, 1 order, 4 families, and 8 genera), after excluding the IVs with linkage disequilibrium (LD). Combining the analysis of the results of the IVW models, there were 6 biological taxa (2 families, and 4 genera) of the intestinal flora positively associated with the risk of AD and 7 biological taxa (1 phylum, 2 classes, 1 order, 1 family, and 2 genera) of the intestinal flora negatively associated. The IVW analysis results showed that Tenericutes, Mollicutes, Clostridia, Bifidobacteriaceae, Bifidobacteriales, Bifidobacterium , and Christensenellaceae R 7 group were negatively correlated with the risk of AD, while Clostridiaceae 1, Bacteroidaceae, Bacteroides, Anaerotruncus, the unknown genus, and Lachnospiraceae UCG001 showed the opposite trend. And the results of the sensitivity analysis were robust. MR Steiger's test showed a potential causal relationship between the above intestinal flora and AD, but not vice versa., Conclusion: The present MR analysis genetically suggests a causal relationship between changes in the abundance of the gut microbiota and AD risk, thus not only providing support for gut microecological therapy of AD but also laying the groundwork for further exploration of the mechanisms by which the gut microbiota contributes to the pathogenesis of AD., 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 Xue, Zhang, Chen, Wang and Xie.)

Two unprecedented aconitine-type C19-diterpenoid alkaloids, refractines A-B ( 1 - 2 ), along with 12 known compounds ( 3 - 14 ) were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand. -Mazz. Their structures were elucidated based on extensive spectroscopic analyses, including 1D and 2D NMR, IR, and HR-ESI-MS data. All compounds were tested for inhibitory activities against NO production in LPS induced RAW 264.7 macrophages, compounds 10 and 14 had slight inhibited NO production with rate of 29.4% and 22.1% at the concentration of 30 μM, respectively.

Ferritin proteins are promising nano-carriers for bioactive compound delivery. However, the disassembly properties under acidic/alkaline conditions pose risks of cargo leakage. Herein, genipin-mediated chemical crosslinking method was provided as an alternative and effective strategy to construct robust ferritin nanocarrier through controlled-intramolecular conjugation. As indicated by SDS-/Native- PAGE, the crosslinking degree gradually increased with incubating time prolonging. CD results showed that the cross-linking would decrease α-helix content from 78.4 % to 52.7 % upon 6 h incubation. However, TEM images showed that the genipin-modification has subtle influence on its shell-like structure. Remarkably, the cross-linking can be well controlled by intramolecular subunit-subunit conjugation rather than intermolecular conjugation, giving an excellent monodispersity. Importantly, the covalent cross-linking can tight neighboring subunits and inhibit its disassociation, finally inhibiting the leakage of encapsulated-cargos from ferritin cavity under acidic environments. Such findings suggested that the genipin-mediated cross-linking strategy can fabricate robust nano-carriers for bioactive compound delivery., 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 © 2023 Elsevier Ltd. All rights reserved.)

Objective: To explore the clinical characteristics and genetic basis of a child with autism spectrum disorder (ASD) in conjunct with congenital heart disease (CHD)., Methods: A child who was hospitalized at the Third People's Hospital of Chengdu on April 13, 2021 was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). A GTX genetic analysis system was used to analyze the WES data and screen candidate variants for ASD. Candidate variant was verified by Sanger sequencing and bioinformatics analysis. Real-time fluorescent quantitative PCR (qPCR) was carried out to compare the expression of mRNA of the NSD1 gene between this child and 3 healthy controls and 5 other children with ASD., Results: The patient, an 8-year-old male, has manifested with ASD, mental retardation and CHD. WES analysis revealed that he has harbored a heterozygous c.3385+2T>C variant in the NSD1 gene, which may affect the function of its protein product. Sanger sequencing showed that neither of his parent has carried the same variant. By bioinformatic analysis, the variant has not been recorded in the ESP, 1000 Genomes and ExAC databases. Analysis with Mutation Taster online software indicated it to be disease causing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. By qPCR analysis, the expression level of mRNA of the NSD1 gene in this child and 5 other children with ASD was significantly lower than that of the healthy controls (P < 0.001)., Conclusion: The c.3385+2T>C variant of the NSD1 gene can significantly reduce its expression, which may predispose to ASD. Above finding has enriched the mutational spectrum the NSD1 gene.

In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids ( 1-8 ), DNP-benzylamine hybrids ( 9-14 ), and DNP-phenylethylamine hybrids ( 15-21 ) were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound 3 exhibited excellent acetylcholinesterase inhibitory activity with an IC 50 value of 4.4 μM, higher than that of positive control DNP and significant neuroprotective effects against H 2 O 2 -induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 μM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound 3 was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound 3 could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: The Chinese population is aging, and chronic non-communicable diseases (NCDs) prevalence is correspondingly increasing, along with associated disability and healthcare costs. Although self-management has been associated with social support and is a recognized priority, its mediating variables have not been studied in detail, particularly among old people with chronic diseases., Purpose: To examine the mediating role of e-health literacy and general self-efficacy in the relationship between social support and self-management of chronic NCDs in Chinese community home-based aging institution residents., Patients and Methods: A random sample of 289 community home-based aging institution elders (≥60 years) with chronic NCDs in China was recruited. Questionnaire data were recorded on self-reported socio-demographics, self-management, social support, e-health literacy, and general self-efficacy. Pearson's correlation analysis identified the relationship between these factors and self-management. Serial multiple mediation model was used to test the hypothesized relationships., Results: The self-management mean (±SD) score was 29.39 ± 9.60, and the level of self-management was medium. Social support (r = 0.283; P < 0.001), e-health literacy (r = 0.566; P < 0.001), and general self-efficacy (r = 0.477; P < 0.001) were positively associated with self-management. Furthermore, social support indirectly influenced self-management through three pathways: independent mediation of e-health literacy (effect = 0.234, P < 0.001), independent mediation of general self-efficacy (effect = 0.515, P < 0.001), and chain mediation of e-health literacy and general self-efficacy (effect = 0.075, P < 0.001)., Conclusion: In Chinese community home-based aging institution elders, the relationship between self-reported self-management and social support is positively affected by the independent mediating effect of e-health literacy and general self-efficacy and the serial mediating effect of e-health literacy and general self-efficacy. Targeted self-management programs for elders with chronic NCDs have theoretical support, which could improve the health status and quality of life in this population., Competing Interests: The authors declare that the study was conducted without any business or financial relationship that could be interpreted as potential conflicts of interest., (© 2023 Wu et al.)

Four new aconitine-type C 19 -diterpenoid alkaloids, were isolated from the roots of Aconitum nagarum Stapf which were named as nagarutines A-D (1-4), together with eleven known compounds (5-15). The structures of the compounds were identified by IR, HR-ESI-MS, 1D and 2D NMR spectra. All compounds were tested for the inhibitory effect on LPS induced NO production in RAW 264.7 macrophages, compound 7 showed moderate anti-inflammatory activity effect and Inhibition rate is about 44.50%., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

The lateral roots of the Aconitum carmichaelii ("Fuzi") have been used for centuries as a cardiotonic in China. The diterpenoid alkaloid talatisamine (TA) is a major bioactive component of Fuzi, but the identity and bioactivities of the TA metabolites have not been examined in detail. In this study, metabolite profiling of TA was performed in rat heart by UPLC-MS following oral administration. Metabolites were identified by comparing protonated molecules, fragmentation patterns, and chromatographic behaviors with those of standard compounds. Metabolites of TA were then prepared and tested for cardiotonic activity on isolated frog hearts. The metabolite cammaconine, a C 19 diterpenoid alkaloid with a hydroxyl group at C-18, exhibited substantial cardiotonic activity during frog heart perfusion. To further investigate the structure-cardiac effect relationships, a series of C 19 -diterpenoid alkaloids with 18-OH were prepared. Eight tested compounds (5: -12: ) demonstrated measurable cardioactivity, of which compound 5: with an N -methyl group and compound 7: with a methoxy at C-16 showed stronger effects on ventricular contraction than the other compounds. Thus, 18-OH is a critical structural feature determining cardiotonic activity, and efficacy is improved by the presence of N -methyl or methoxy at C-16. Preliminary mechanistic studies suggested that the cardiotonic effect of compound 5: is mediated by enhanced cellular calcium influx. Metabolites of TA with these structural features may be useful therapeutics to prevent heart failure., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: To determine the independent predictive role of nasal obstruction in resistant hypertension (RH) in uncontrolled hypertensive patients with obstructive sleep apnea (OSA)., Methods: This prospective cohort study comprised of 236 OSA patients with uncontrolled blood pressure (BP) using 1 or 2 classes of antihypertensive drugs visiting Sleep Medicine Center from April 2021 to March 2022. Information on demographic characteristics, comorbidities, BP control and classes of antihypertensive medication, sleep-related symptoms, Nasal Obstruction Symptom Evaluation (NOSE) Scale and sleep parameters was collected. RH incidence according to the BP control and classes of antihypertensive drugs data during the 5 month follow-up was collected., Results: After 5 month follow-up, 217 participants were included for final data analysis. Ninety-five subjects had nocturnal nasal obstruction with a higher proportion of RH (36.8% vs. 17.2%, p = 0.001) compared to those without nocturnal nasal obstruction. After adjustment for demographic characteristics, sleep-related symptoms and OSA severity, multinomial logistic regression models showed that nocturnal nasal obstruction (all ORs > 2.5, p < 0.05) or NOSE ≥ 8 (all ORs > 4.5, p < 0.05) was independently associated with a higher odds of RH. Nasal obstruction treatment improved NOSE score significantly, but did not reduce the incidence of RH significantly. Effective nasal obstruction treatment was associated with antihypertensive drugs reduction (OR 4.43; 95% CI 1.20-16.27)., Conclusions: Nasal obstruction is an independent predictor of RH in uncontrolled hypertensive patients with OSA. In addition to the treatment of OSA, assessment and treatment of nasal obstruction should be considered in the management of uncontrolled hypertensive patients with OSA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The gut-brain axis has been widely recognized in autism spectrum disorder (ASD), and probiotics are considered to potentially benefit the rescuing of autism-like behaviors. As a probiotic strain, Lactiplantibacillus plantarum N-1 ( LPN-1 ) was utilized to investigate its effects on gut microbiota and autism-like behaviors in ASD mice constructed by maternal immune activation (MIA)., Methods: Adult offspring of MIA mice were given LPN-1 at the dosage of 2  ×  10 9   CFU/g for 4  weeks before subject to the behavior and gut microbiota evaluation., Results: The behavioral tests showed that LPN-1 intervention was able to rescue autism-like behaviors in mice, including anxiety and depression. In which the LPN-1 treatment group increased the time spent interacting with strangers in the three-chamber test, their activity time and distance in the central area increased in the open field test, and their immobility time decreased when hanging their tails. Moreover, the supplementation of LPN-1 reversed the intestinal flora structure of ASD mice by enhancing the relative abundance of the pivotal microorganisms of Allobaculum and Oscillospira , while reducing those harmful ones like Sutterella at the genus level., Discussion: These results suggested that LPN-1 supplementation may improve autism-like behaviors, possibly via regulating the gut microbiota., 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 Qiu, Luo, Yin, Chen, Zhou, Zhang, Zhang, Xia, Xie, Sun and Xu.)

The risk assessment of carotid plaque is strongly related to the plaque echo status in ultrasound. However, the echo classification of carotid plaques based on ultrasound remains challenging due to the changes in plaque shape and semantics, along with the complex vascular environment. This study proposed a framework for Classification of Plaque by Tracking Videos (CPTV). To the best of our knowledge, this is the first study on plaque classification by tracking ultrasound video rather than a sonographic view, which achieves accurate localization and stable echo classification. In the tracking task, Multi-scale Decoupling Tracking (MDTrack) module including Multi-scale Dilated Encoder (MDE) and Internal-Exterior Feature Decoupling (IEFD) was proposed to solve the problems caused by shape and semantic variations to achieve accurate plaque localization in ultrasound. In the classification task, the Tracking-assisted 3D Attention (T3D-Attention) module included recombination and 3D-Attention extracted plaque features and echo-related features in the vascular environment. The experiments demonstrated that the performance of CPTV is better than current mainstream tracking and classification methods, indicating that the tracking-assistance classification is a kind of enhancement method with high universality and stability in the plaque in ultrasound., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Autism spectrum disorders (ASD) is a neurodevelopmental disorder with high incidence rate and difficult diagnosis. The purpose of this study was to explore whether salivary cortisol, dehydroepiandrosterone (DHEA) and pregnenolone can be used as biomarkers of ASD children., Methods: The saliva samples of 55 boys with ASD were collected as the experimental group, and the saliva samples of 24 neurotypical boys were collected as the control group. The Child Behavior Checklist (CBCL), Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), Repetitive Behavior Scale (RBS) were used to assess the severity of symptoms in boys with ASD. Cortisol, DHEA and pregnenolone concentrations in saliva were measured using an ABSSCIEX QTRAP® 6500 + LC/MS/MS system. SPSS 23.0 was used for statistical analysis. Comparisons between the two groups which conform to normal distribution were performed by T-test, and those which don't conform to normal distribution were performed by Mann-Whitney U test. Correlation analysis between two variables was performed using Spearman's correlation analysis. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the discriminatory sensitivity of each hormone between ASD and normal control groups. Logistic regression models were used to analyze whether DHEA and salivary pregnenolone can be used as a biomarker of ASD., Results: There were no significant differences in age, and weight between the ASD group and the normal control group. The ABC, SRS, RBS and CBCL scale scores in the ASD group were significantly higher than those in the normal control group. The salivary DHEA and pregnenolone concentrations in the ASD group were significantly higher than those in the normal control group, but there was no significant difference in cortisol. Spearman's correlation analysis showed that only pregnenolone associated with ABC. Logistic regression model analysis suggested that pregnenolone in saliva was an independent predictor of ASD. ROC analysis found that pregnenolone had good discrimination sensitivity between ASD and normal controls., Conclusion: Gave salivary preoperative a space for utilization as biomarker as number of cases are limited to this high expectation., (© 2023. The Author(s).)