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Abstract Background Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear. Methods A hyperhomocysteinemia atherosclerotic model with ApoE−/− mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis. Results We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1β, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis. Conclusion Homocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.

Abstract Background Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Methods Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p

Most real-time semantic segmentation networks use shallow architectures to achieve fast inference speeds. This approach, however, limits a network’s receptive field. Concurrently, feature information extraction is restricted to a single scale, which reduces the network’s ability to generalize and maintain robustness. Furthermore, loss of image spatial details negatively impacts segmentation accuracy. To address these limitations, this paper proposes a Multiscale Context Pyramid Pooling and Spatial Detail Enhancement Network (BMSeNet). First, to address the limitation of singular semantic feature scales, a Multiscale Context Pyramid Pooling Module (MSCPPM) is introduced. By leveraging various pooling operations, this module efficiently enlarges the receptive field and better aggregates multiscale contextual information. Moreover, a Spatial Detail Enhancement Module (SDEM) is designed, to effectively compensate for lost spatial detail information and significantly enhance the perception of spatial details. Finally, a Bilateral Attention Fusion Module (BAFM) is proposed. This module leverages pixel positional correlations to guide the network in assigning appropriate weights to the features extracted from the two branches, effectively merging the feature information of both branches. Extensive experiments were conducted on the Cityscapes and CamVid datasets. Experimental results show that the proposed BMSeNet achieves a good balance between inference speed and segmentation accuracy, outperforming some state-of-the-art real-time semantic segmentation methods.

Deep learning has recently made significant progress in semantic segmentation. However, the current methods face critical challenges. The segmentation process often lacks sufficient contextual information and attention mechanisms, low-level features lack semantic richness, and high-level features suffer from poor resolution. These limitations reduce the model’s ability to accurately understand and process scene details, particularly in complex scenarios, leading to segmentation outputs that may have inaccuracies in boundary delineation, misclassification of regions, and poor handling of small or overlapping objects. To address these challenges, this paper proposes a Semantic Segmentation Network Based on Adaptive Attention and Deep Fusion with the Multi-Scale Dilated Convolutional Pyramid (SDAMNet). Specifically, the Dilated Convolutional Atrous Spatial Pyramid Pooling (DCASPP) module is developed to enhance contextual information in semantic segmentation. Additionally, a Semantic Channel Space Details Module (SCSDM) is devised to improve the extraction of significant features through multi-scale feature fusion and adaptive feature selection, enhancing the model’s perceptual capability for key regions and optimizing semantic understanding and segmentation performance. Furthermore, a Semantic Features Fusion Module (SFFM) is constructed to address the semantic deficiency in low-level features and the low resolution in high-level features. The effectiveness of SDAMNet is demonstrated on two datasets, revealing significant improvements in Mean Intersection over Union (MIOU) by 2.89% and 2.13%, respectively, compared to the Deeplabv3+ network.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.

Although the Japanese encephalitis virus (JEV) infects various cell types, its receptor molecules are still not clearly understood. In our laboratory’s prior research, Rab4b was identified as a potential host factor that facilitates JEV infection in PK15 cells, utilizing a genome-wide CRISPR/Cas9 knockout library (PK-15-GeCKO). To further explore the effect of Rab4b on JEV replication, we used the Rab4b knockout PK15 cell line using the CRISPR/Cas9 technology and overexpressing the Rab4b PK15 cell line, with IFA, RT–qPCR, and Western blot to study the effect of Rab4b on viral replication in the whole life cycle of the JEV. The results show that the knockout of Rab4b inhibited the replication of the JEV in PK15 cells, and the overexpression of Rab4b promoted the replication of the JEV in PK15 cell lines. Furthermore, we demonstrated for the first time that host factor Rab4b facilitates the adsorption, internalization, assembly, and release of the JEV, thereby promoting JEV replication. This study enriches the regulatory network between the JEV and host factors and lays the experimental foundation for further understanding of the function of the Rab4b protein.

Background: Perioperative neurocognitive disorders (PNDs) were the most common complication in elderly patients undergoing surgery. Early identification of risk factors for PNDs and implementation of preventive measures were critical to improve prognosis. We performed this systematic review and meta-analysis to explore the impact of preoperative frailty on PNDs in elderly surgical patients. Materials and Methods: Systematic searches were performed in PubMed, Embase, and Web of Science. A fixed-effect model in RevMan5.3 software was conducted due to the low heterogeneity. The potential risk bias was assessed through Funnel plot and Egger’s test. Sensitivity analysis was used to examine the robustness of the outcomes. Results: Sixteen cohort studies enrolling 4805 elderly patients were qualified for meta-analysis. Pooled results showed that preoperative frailty was linked to the development of PNDs (pooled odds ratio [OR]: 2.40, 95% confidence interval [CI]: 2.05–2.80, P < 0.001) without obvious heterogeneity (P = 0.19, I2 = 22%). Subgroup analyses revealed that the correlation between preoperative frailty and PNDs was more remarkable in prospective cohort studies (OR: 3.11, 95% CI: 2.47–3.91, P < 0.001) compared to retrospective cohort studies (OR: 1.94, 95% CI: 1.57–2.39, P < 0.001; test for subgroup difference, P = 0.003). In addition, the correlation in patients with cardiac surgery (OR: 3.38, 95% CI: 2.44–4.68, P < 0.001) was more noticeable than noncardiac surgery (OR: 2.17, 95% CI: 1.82–2.59, P < 0.001; test for subgroup difference P = 0.02). Conclusion: Our results demonstrated that preoperative frailty was independently associated with PNDs in geriatric patients undergoing elective surgery.

The power sector is one of the major CO2-emitting industries in China. It is also the first key emissions control industry included in China’s national carbon trading market established in 2021. Therefore, based on the data of 30 provinces and cities in China from 2015 to 2022, this study analyzes the impact of the national carbon market policy on the carbon emissions of the power industry based on the generalized Difference-in-Difference (DID) model. Based on the method of text analysis, this paper constructs the carbon market policy intensity index of each region and incorporates it into the DID model. Empirical analysis finds that the national carbon market policy can significantly inhibit the carbon emissions of the power industry. However, the heterogeneity analysis of 30 provinces and cities shows that the national carbon market policy has a significant impact on the regions that already have a carbon pilot, but not on the non-pilot regions. Therefore, this paper demonstrates the effectiveness of the national carbon market policy in the power industry emissions control, and also exposes the heterogeneity between regions, providing an important empirical basis for the inclusion of other energy-intensive industries.

Background: Prepubertal girls are one of the vulnerable populations of vulvar lichen sclerosus (VLS), which results in a decreased quality of life and increases risk of vulvar cancer. But the therapeutic effects of traditional topical remedies are unsatisfactory in some pediatric patients. 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective treatment for refractory VLS patients, but no study has been conducted in child patients. Methods: The patients included in this study underwent three sessions of ALA-PDT at 2-week intervals. All patients were evaluated for objective clinical appearances and subjective symptoms quantitatively. Statistical analysis comparing parameters at baseline and after three-time ALA-PDT was performed. Results: A total of seven VLS girl patients were included in this study. Both primary objective appearances (lesion size and depigmentation) and subjective symptoms (itching and burning pain) were improved remarkably after the third treatment. Besides, adverse effects, mainly as pain and post-treatment edema, were mild and could be tolerated. Conclusions: ALA-PDT is an effective and safe therapeutic option for VLS girl patients. Compared with adult patients, the symptoms resolved more quickly in child patients.

Background: Micheliolide (MCL), which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear. Method: ApoE−/− mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected. Results: MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abrogate the anti-ferroptosis and anti-oxidative effects of MC in macrophages. KEAP1-R483S mutation also limited the protective effect of MCL on atherosclerosis progress and macrophage ferroptosis in ApoE−/− mice. Conclusion: MCL suppressed atherosclerosis by inhibiting macrophage ferroptosis via activating NRF2 pathway, the related mechanism is through binding to the Arg483 site of KEAP1 competitively.

Coronary heart disease (CHD) is an abbreviation of coronary atherosclerotic heart disease, which remains challenging for diagnosis and treatment. Current study aims to explore the correlation between geriatric nutritional risk index (GNRI) and osteoporosis, sarcopenia, cognitive dysfunction in elderly patients with CHD, and to analyze the clinical diagnostic value of GNRI in the above complications. A total of 92 elderly patients with CHD treated in Suzhou Ninth People's Hospital from January 2020 to October 2023 were retrospectively collected as the experimental group, and 68 non-CHD subjects matched for sex and age in the same period of physical examination were randomly selected as the control group. Osteoporosis, sarcopenia and cognitive dysfunction were analyzed in all patients, and the correlation between GNRI and these indices in different populations was analyzed by Spearman's rank correlation. The diagnostic efficacy of GNRI in osteoporosis, sarcopenia, and cognitive impairment was analyzed by ROC curves. There was no significant difference in age, sex distribution, body mass index (BMI) and serum biological indexes between the elderly patients with CHD and the control group (all P > 0.05). Correlation analysis showed that GNRI level was positively correlated with bone mineral content (BMC), bone mineral density (BMD) T value and osteocalcin (OCN) (All r > 0, P 0, P 0.05). In the elderly and elderly with CHD, the diagnostic AUC of GNRI was 0.875 and 0.862 in osteoporosis, and 0.912 and 0.932 in sarcopenia, respectively. The level of GNRI is significantly correlated with osteoporosis and sarcopenia. GNRI level, as an auxiliary diagnostic tool in elderly patients with CHD, exerts important clinical significance for early detection of the risk of complications, such as osteoporosis and sarcopenia.

Abstract Object detection on fused images of visible and infrared modals is of great importance for many applications, for example, surveillance and rescue at low‐light conditions. However, current detectors have difficulty for robust fused image detection for mainly two reasons. First, objects are presented in various shapes and sizes, making some hard samples cannot be localized accurately. Second, the same object category in the fused images will have different appearance due to changing weather condition, temperature and intrinsic heat. Such a contradiction will degrade the classification task of a detection network, since it cannot merge commonalities and distinguish differences well. In this paper, we propose to reconstruct the detection pipeline of current detectors, and enhance the detection ability on difficult samples in fused images. Specifically, a Dilation Pyramid Network (DPN) is designed at the lateral connection to generate and aggregate features of various receptive field, without increasing pyramid layers. To strengthen the classification, a Semantic Category Attention Module (SCAM) is proposed to capture attention centers of semantics in fused images, rather than object centers. Abundant experiments on two fusion datasets show that the proposed method achieves a satisfying performance, and both modules can greatly improve current generic detectors on fused images.

This study aimed to investigate the effects of physical multimorbidity on the trajectory of cognitive decline over 17 years and whether vary across wealth status. The study was conducted in 9035 respondents aged 50+ at baseline from nine waves (2002–2019) of the English Longitudinal Study of Aging. A latent class analysis was used to identify patterns of physical multimorbidity, and mixed multilevel models were performed to determine the association between physical multimorbidity and trajectories of cognitive decline. Joint analyses were conducted to further verify the influence of wealth status. Four patterns of physical multimorbidity were identified. Mixed multilevel models with quadratic terms of time and status/patterns indicated significant non-linear trajectories of multimorbidity on cognitive function. The magnitude of the association between complex multisystem patterns and cognitive decline increased the most as follow-up progressed. Individuals with high wealth and hypertension/diabetes patterns have significantly lower composite global cognitive z scores over time as compared with respiratory/osteoporosis patterns. Physical multimorbidity at baseline is associated with the trajectory of cognitive decline, and the magnitude of the association increased over time. The trend of cognitive decline differed in specific combinations of wealth status and physical multimorbidity.

BackgroundIn recent years, remarkable progress has been made in the use of machine learning, especially in analyzing prognosis survival data. Traditional prediction models cannot identify interrelationships between factors, and the predictive accuracy is lower. This study aimed to construct Bayesian network models using the tree augmented naïve algorithm in comparison with the Cox proportional hazards model.MethodsA Bayesian network model and a Cox proportional hazards model were constructed to analyze the prognostic factors of endometrial cancer. In total, 618 original cases obtained from the Surveillance, Epidemiology, and End Results database were used to construct the Bayesian network model, which was compared with the traditional Cox proportional hazards model by analyzing prognostic factors. External validation was performed using a dataset from The First Affiliated Hospital of Shandong First Medical University.ResultsThe predictive accuracy, area under the receiver operating characteristic curve, and concordance index for the Bayesian network model were 74.68%, 0.787, and 0.72, respectively, compared to 68.83%, 0.723, and 0.71, respectively, for the Cox proportional hazards model. Tumor size was the most important factor for predicting survival, followed by lymph node metastasis, distant metastasis, chemotherapy, lymph node resection, tumor stage, depth of invasion, tumor grade, histological type, age, primary tumor site, radiotherapy and surgical sequence, and radiotherapy.ConclusionThe findings indicate that the Bayesian network model is preferable to the Cox proportional hazards model for predicting survival in patients with endometrial cancer.

The crustacean hyperglycemic hormone (CHH) is a multifaceted neuropeptide instrumental in regulating carbohydrate and lipid metabolism, reproduction, osmoregulation, molting, and metamorphosis. Despite its significance, there is a dearth of research on its metabolic impact on the gills and epidermis—key organs in osmoregulation and molting processes. This study employed CHH dsRNA injections to silence CHH gene expression in Procambarus clarkii, followed by a metabolomic analysis of the gills and epidermis using nuclear magnetic resonance spectroscopy. Metabolic profiling through principal component analysis revealed the most pronounced changes at 24 h post-injection (hpi) in the epidermis and at 48 hpi in the gills. At 24 hpi, the epidermis exhibited significant modulation in 25 enrichment sets and 20 KEGG pathways, while at 48 hpi, 5 metabolite sets and 6 KEGG pathways were prominently regulated. Notably, pathways associated with amino acid metabolism, carbohydrate metabolism, and cofactor and vitamin metabolism were affected. A marked decrease in glucose and other carbohydrates suggested a compromised carbohydrate supply, whereas increased levels of citrate cycle intermediates implied a potential boost in energy provision. The silencing of CHH gene expression hampered the carbohydrate supply, which was possibly the main energy derived substrates. Conversely, the gills displayed significant alterations in 15 metabolite sets and 16 KEGG pathways at 48 hpi, with no significant changes at 24 hpi. These changes encompassed amino acid, carbohydrate, and lipid metabolism pathways. The decline in TCA cycle intermediates pointed to a potential downregulation of the cycle, whereas a decrease in ketone bodies indicated a shift towards lipid metabolism for energy production. Additionally, increased levels of nicotinate, nicotinamide, and quinolinate were observed in both organs. Overall, CHH’s impact on the epidermis was prominent at 24 hpi and diminished thereafter, whereas its influence on metabolism in gills was delayed but intensified at 48 hpi. This differential CHH effect between gills and epidermis in P. clarkii provides new insights into the organ-specific regulatory mechanisms of CHH on energy metabolism and osmoregulation, warranting further comparative studies to elucidate the distinct roles of CHH in these organs.

Coxiella burnetii is an obligate intracellular bacterium that causes Q fever, a zoonotic disease typically manifests as a severe flu-illness. After invading into the host cells, C. burnetii delivers effectors to regulate the vesicle trafficking and fusion events to form a large and mature Coxiella-containing vacuole (CCV), providing sufficient space and nutrition for its intracellular growth and proliferation. Lysosomal trafficking regulator (LYST) is a member of the Beige and Chediak-Higashi syndrome (BEACH) family, which regulates the transport of vesicles to lysosomes and regulates TLR signaling pathway, but the effect of LYST on C. burnetii infection is unclear. In this study, a series of experiments has been conducted to investigate the influence of LYST on intracellular growth of C. burnetii. Our results showed that lyst transcription was up-regulated in the host cells after C. burnetii infection, but there is no significant change in lyst expression level after infection with the Dot/Icm type IV secretion system (T4SS) mutant strain, while CCVs expansion and significantly increasing load of C. burnetii appeared in the host cells with a silenced lyst gene, suggesting LYST inhibits the intracellular proliferation of C. burnetii by reducing CCVs size. Then, the size of CCVs and the load of C. burnetii in the HeLa cells pretreated with E-64d were significantly decreased. In addition, the level of iNOS was decreased significantly in LYST knockout THP-1 cells, which was conducive to the intracellular replication of C. burnetii. This data is consistent with the phenotype of L-NMMA-treated THP-1 cells infected with C. burnetii. Our results revealed that the upregulation of lyst transcription after infection is due to effector secretion of C. burnetii and LYST inhibit the intracellular replication of C. burnetii by reducing the size of CCVs and inducing nos2 expression.

BackgroundDelirium is a common complication among intensive care unit (ICU) patients that is linked to negative clinical outcomes. However, adherence to the Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS guidelines), which recommend the use of the ABCDEF bundle, is sub-optimal in routine clinical care. To address this issue, AI-AntiDelirium, a nurse-led artificial intelligence-assisted prevention and management tool for delirium, was developed by our research team. Our pilot study yielded positive findings regarding the use of AI-AntiDelirium in preventing patient ICU delirium and improving activities of daily living and increasing intervention adherence by health care staff.MethodsThe proposed large-scale pragmatic, open-label, parallel-group, cluster randomized controlled study will assess the impact of AI-AntiDelirium on the incidence of ICU delirium and delirium-related outcomes. Six ICUs in two tertiary hospitals in China will be randomized in a 1:1 ratio to an AI-AntiDelirium or a PADIS guidelines group. A target sample size of 1,452 ICU patients aged 50 years and older treated in the ICU for at least 24 hours will be included. The primary outcome evaluated will be the incidence of ICU delirium and the secondary outcomes will be the duration of ICU delirium, length of ICU and hospital stay, ICU and in-hospital mortality rates, patient cognitive function, patient activities of daily living, and ICU nurse adherence to the ABCDEF bundle.DiscussionIf this large-scale trial provides evidence of the effectiveness of AI-AntiDelirium, an artificial intelligence-assisted system tool, in decreasing the incidence of ICU delirium, length of ICU and hospital stay, ICU and in-hospital mortality rates, patient cognitive function, and patient activities of daily living while increasing ICU nurse adherence to the ABCDEF bundle, it will have a profound impact on the management of ICU delirium in both research and clinical practice.Clinical trial registrationChiCTR1900023711 (Chinese Clinical Trial Registry).

Background. Da-Chuan-Xiong Decoction (DCXD) is an aqueous extract from a classic Chinese herbal formula composed of dried rhizomes of Ligusticum chuanxiong Hort and Gastrodia elata Bl. in the mass ratio of 4 : 1. It has been long used to treat chronic cardiovascular disease caused by blood stasis and wind pathogen in the clinic. This experimental study aimed to investigate the blood pressure (BP)-lowering effect of DCXD treatment on hypertension and underlying mechanisms. Methods. Male Sprague–Dawley rats were used in the experiment, and the hypertensive models were created by administering deoxycorticosterone acetate (DOCA) in conjunction with a high salt intake in uninephrectomized rats. DCXD was administered to hypertensive rats by oral gavage daily at a dose of 5 g/kg or 2.5 g/kg bodyweight for 28 days. The brain sodium sensitivity, ENaC function, superoxide anion level, NADPH oxidase activity, and expression of ENaC, p67phox, p47phox, and Rac1 in the paraventricular nucleus were assessed by using the appropriate methods. Results. The 28 days of DCXD (5 g/kg) treatment significantly reduced the increased BP effectively, inhibited the enhanced heart index, kidney index, and 24 h urinary protein, and improved the progressive pathological changes of heart and kidney, which was comparable to that of the positive control amlodipine. DCXD treatment also caused a marked reduction in plasma norepinephrine and induced a significant improvement in brain sodium sensitivity and ENaC function in DOCA-salt hypertensive rats. Rats in DCXD-treated groups also exhibited decreased superoxide anion levels and NADPH oxidase activity in the paraventricular nucleus. The level of ENaC, p67phox, and Rac1 protein expression in the paraventricular nucleus was significantly downregulated by DCXD treatment in DOCA-salt hypertensive rats. Conclusions. These findings indicate that the depressor action and sympathetic inhibition of DCXD on salt-sensitive hypertension may be by ameliorating brain sodium sensitivity, modulating ENaC function, and inhibiting the expression of ENaC and NADPH oxidase in the hypothalamic paraventricular nucleus.

Lipids are important tea aroma precursors. Due to the complexity of black tea processing involving both enzymatic and thermal reactions, the role of lipids in black tea aroma formation remained unclear. Herein, the dynamic changes of lipids and volatiles during black tea processing were simultaneously analyzed by lipidomics and volatolomics using ultra-high-performance liquid chromatography coupled to Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive) and gas chromatography-tandem mass spectrometry (GC-MS/MS). The lipidomics method was validated in linearity, reproducibility, and recovery, which showed a high reliability. A total of 374 lipids and 88 volatiles were detected. Among them, 362 lipids and 29 fatty acid-derived volatiles (FADVs) were significantly altered depending on different processing stages. During the enzyme-driven stages of black tea processing (withering, rolling and fermentation), monogalactosyldiacylglycerol (MGDG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) were largely downregulated (

ABSTRACTObjective To identify biomarkers that can predict the recurrence of the central nervous system (CNS) in children with acute lymphoblastic leukemia (ALL).Materials and Methods The transcriptome and clinical data of ALL in children were downloaded from the TARGET database. Transcriptome data were analyzed by bioinformatics method to identify core (hub) genes and establish a risk assessment model. Univariate Cox analysis was performed on each clinical data, and multivariate Cox regression analysis was performed on the obtained results and risk score. The children ALL phase I samples from TARGET database were used for validation.Results Univariate multivariate Cox analysis of 10 hub genes identified showed that PPARG (HR = 0.78, 95%CI = 0.67–0.91, p = 0.007), CD19 (HR = 1.15, 95%CI = 1.05–1.26, p = 0.003) and GNG12 (HR = 1.25, 95%CI = 1.04–1.51, p = 0.017) had statistical differences. The risk score was statistically significant in univariate (HR = 3.06, 95%CI = 1.30–7.19, p = 0.011) and multivariate (HR = 1.81, 95%CI = 1.16–2.32, p = 0.046) Cox regression analysis. The survival analysis results of the high and low-risk groups were different when the validation dataset was substituted into the model (p = 0.018). Then, we constructed a Nomogram which had a concordance index of survival prediction of 0.791(95%CI= 0.779-0.803). In addition, the CNS involvement grading status at first diagnosis CNS3 vs. CNS1 (HR = 5.74, 95%CI = 2.01–16.4, p = 0.001), T cell vs B cell (HR = 1.63, 95% CI = 1.06-2.49, p = 0.026) were also statistically significant.Conclusions PPARG, GNG12, and CD19 may be predictors of CNS relapse in childhood ALL.

Rolling represents an essential stage in congou black tea processing. However, the influence of rolling pressure on tea flavor and non-volatile compounds remains unclear. Herein, a combination of untargeted metabolomics, tea pigments quantification, E-tongue, colorimeter and sensory evaluation was used to evaluate the effect of rolling pressure on black tea quality. As the rolling pressure increased, theaflavins (TFs), thearubigins (TRs), and theabrownins (TBs) significantly elevated. The tea metabolic profiles fluctuated and 47 metabolites were identified as key differential metabolites including flavan-3-ols, flavonol/flavone glycosides, phenolic acids, amino acids. These substances altered possibly due to the variations in enzymatic oxidation of tea phenolics and amino acids. Overall, black tea with moderate rolling pressure presented higher sweetness, lower bitterness, and higher quality index (10 TFs + TRs)/TBs. The results were verified by a validation batch. This study provided new insights into the regulation of rolling pressure and a guidance for black tea processing.

Hyperlipidemia is a frequent metabolic disorder that is closely associated with diet. It is believed that brown rice, containing the outer bran layer and germ, is beneficial for the remission of hyperlipidemia. This study established a rat model of hyperlipidemia by feeding a high-fat diet. The hypolipidemic potential of germinated brown rice (Gbrown) and germinated black rice (a germinated black-pigmented brown rice, Gblack) were explored in the model rats, mainly in the aspects of blood lipids, lipases, apolipoproteins, and inflammation. The gut microbiota in hyperlipidemic rats receiving diverse dietary interventions was determined by 16S rDNA sequencing. The results showed that the intervention of Gbrown/Gblack alleviated the hyperlipidemia in rats, evidenced by decreased TC, TG, LDL-C, and apolipoprotein B, and increased HDL-C, HL, LPL, LCAT, and apolipoprotein A1. Gbrown/Gblack also weakened the inflammation in hyperlipidemia rats, evidenced by decreased TNF-α, IL-6, and ET-1. In addition, 16S rDNA sequencing revealed that the diet of Gbrown/Gblack elevated the abundance and diversity of gut microbiota in hyperlipidemia rats. At the phylum level, Gbrown/Gblack decreased Firmicutes, increased Bacteroidetes, and decreased the F/B ratio in hyperlipidemia rats. At the genus level, Gbrown/Gblack decreased Streptococcus and increased Ruminococcus and Allobaculum in hyperlipidemia rats. Some differential microbial genera relating to lipid metabolism were also determined, such as the Lachnospira and Ruminococcus in the Gblack group, and the Phascolarctobacterium, Dorea, Turicibacter, and Escherichia-Shigella in the Gbrown group. Notably, the beneficial effect of Gblack was stronger than Gbrown. To sum up, the dietary interventions of Gbrown/Gblack contributed to the remission of hyperlipidemia by alleviating the dysbiosis of gut microbiota.

To generate antibodies with different effector functions, B cells undergo Immunoglobulin Heavy Chain (IgH) class switch recombination (CSR). The ligation step of CSR is usually mediated by the classical nonhomologous end-joining (cNHEJ) pathway. In cNHEJ-deficient cells, a remarkable ~25% of CSR can be achieved by the alternative end-joining (Alt-EJ) pathway that preferentially uses microhomology (MH) at the junctions. While A-EJ-mediated repair of endonuclease-generated breaks requires DNA end resection, we show that CtIP-mediated DNA end resection is dispensable for A-EJ-mediated CSR using cNHEJ-deficient B cells. High-throughput sequencing analyses revealed that loss of ATM/ATR phosphorylation of CtIP at T855 or ATM kinase inhibition suppresses resection without altering the MH pattern of the A-EJ-mediated switch junctions. Moreover, we found that ATM kinase promotes Alt-EJ-mediated CSR by suppressing interchromosomal translocations independent of end resection. Finally, temporal analyses reveal that MHs are enriched in early internal deletions even in cNHEJ-proficient B cells. Thus, we propose that repetitive IgH switch regions represent favored substrates for MH-mediated end-joining contributing to the robustness and resection independence of A-EJ-mediated CSR. [ABSTRACT FROM AUTHOR]

Abstract Objectives Pseudomyogenic hemangioendothelioma (PHE) is a rare intermediate hemangioendothelioma. This article aims to study the clinicopathological features of PHE. Methods We collected the clinicopathological features of 10 new PHE, and examined their molecular pathological features by fluorescence in situ hybridization. In addition, we summarized and analyzed the pathological data of 189 reported cases. Results The case group consisted of six men and four women aged 12–83 years (median: 41 years). Five instances occurred in the limbs, three in the head and neck, and two in the trunk. Tumor tissues were composed of spindle cells and round or polygonal epithelioid cells, which were either arranged in sheets or interwoven, along with areas of transitional morphology. Scattered or patchy stromal neutrophil infiltration was observed. Tumor cells had abundant cytoplasm, and some contained vacuoles. The nuclei had mild to moderate atypia, with visible nucleoli, and mitosis was rare. PHE tissues diffusely expressed CD31 and ERG, but not CD34, Desmin, SOX-10, HHV8 or S100, while some samples expressed CKpan, FLI-1 and EMA. INI-1 stain is retained. The proliferation index of Ki-67 is 10–35%. Seven samples were detected by fluorescence in situ hybridization, six of which had breakages in FosB proto-oncogene (AP-1 transcription factor subunit). Two patients experienced recurrence; however, no metastasis or death occurred. Conclusions PHE is a rare soft tissue vascular tumor, which has biologically borderline malignant potential, local recurrence, little metastasis, and good overall survival and prognosis. Immunomarkers and molecular detection are valuable for diagnosis.

Utilizing four nested domains of large eddy simulation with Weather Research and Forecasting Model （WRF-LES）， this paper carries out wind simulation test in Chongli area， where is one of the host locations of 2022 Beijing Winter Olympics.Based on surface and lidar data， a clear-sky case with high-pressure system is chosen to evaluate the performance of the model.STRM1 30 m topographic data， glc2015 27 m land use data， and China Meteorological Administration Land Data Assimilation （CLDAS） soil moisture data are introduced to improve the simulated results.In addition， sensitive tests are conducted to evaluate effects of different input data.Results show that： （1） Spatial and temporal changes of simulated winds reasonably agree with observations.The mean absolute error （MAE） of wind direction is 10°~60° and the wind speed is 0.8~2 m·s-1.For wind direction， errors of higher-elevation areas are less than that of lower-elevation areas.The errors are less during the developed period of valley-wind or slope-wind but grow higher when wind shifts.（2） Positive effects are concluded after the update of terrain， land use and soil moisture data.The improvements are most obvious for both wind direction and 2-meter temperature after using CLDAS soil moisture， with MAE values reduced by 4.26° and 0.84 °C， respectively.The wind speed is more sensitive to land use， and the error is reduced by 0.32 m·s-1.（3） The CLDAS soil moisture is obviously lower than that of ERA5.Lower soil moisture can create lower conductivity or lower heat capacity， this state can create stronger surface warming during daytime and cooling at night， and the vertical height of the stronger daytime warming can reach 700~900 m， while the intense nighttime cooling is below 200 m.An apparent wind increase is also noted in lower layers during daytime.These changes are more obvious in valleys and ravines.

Hydroxyapatite (HA), an artificial bioceramic with high similarity to the mineral constituent of vertebrate bones and teeth, has attracted extensive attention due to its excellent bioactivity and biocompatibility. The micro-nano structure of HA is a vital factor in expanding its application in biomedicine as well as in many other industrial fields. What's more, HA nanofiber exhibits outstanding properties among its various morphologies. In this work, HA bundles with the same oriented nanofibers are successfully synthesized in a solvothermal reaction system by controlling the amount of carbonate addition and using oleic acid as a template. Under the synergistic effect of different molar ratios of hydroxide ion to carbanion ([OH−]/[CO32−]), HA nanofibers gradually increase their aspect ratio and tend to grow into oriented bundles. This product has admirable flexibility and good mechanical strength, as well as great application potential. Based on the characterization and analysis results, we take a further exploration of the effects of ionic interference ([OH−]/[CO32−]) and charge balance (CO32− vs PO43, Na + vs Ca2+) on the microstructure, phase composition and thermal stability of HA nanofibers bundles (HANBs) in the solvothermal system during the chemical reaction process. And then, the formation and assembly mechanism of HANBs is proposed, and the role of van der Waals forces in this process is also discussed. Furthermore, the generation of this clustered state may be influenced by the shift in the dissolution equilibrium of insoluble carbonates during synthesis. This research provides a new direction for controlling the micro-nano morphology of HA to further obtain products with desirable properties.

This paper presents a novel method for registering panoramic images and 3D point clouds using the shape of the overall ground object in the scene as registration primitives. Firstly, a semantic segmentation method is applied to the panoramic image to extract the ground object and remove the sky. Next, the cloth simulation filtering algorithm (CSF) is employed to eliminate the ground points in the 3D point cloud. The remaining 3D ground objects are then projected onto a two-dimensional plane using the imaging model of the panoramic camera to obtain the registration primitives. Finally, we adopt the whale algorithm to perform a coarse-to-fine registration, utilizing overlap degree and mutual information as the similarity measures. The proposed method is evaluated in four different scenes and compared with the other four registration methods. The results demonstrate that the proposed method is accurate and effective, with an average registration error of 11.48 pixels (image resolution is $11000\times 5500$ pixels) compared to the EOPs of the system of 101.67 pixels.

Abstract Background Health interventions can delay or prevent the occurrence and development of diabetes. Dynamic nomogram and risk score (RS) models were developed to predict the probability of developing type 2 diabetes mellitus (T2DM) and identify high-risk groups. Methods Participants (n = 44,852) from the Beijing Physical Examination Center were followed up for 11 years (2006–2017); the mean follow-up time was 4.06 ± 2.09 years. Multivariable Cox regression was conducted in the training cohort to identify risk factors associated with T2DM and develop dynamic nomogram and RS models using weighted estimators corresponding to each covariate derived from the fitted Cox regression coefficients and variance estimates, and then undergone internal validation and sensitivity analysis. The concordance index (C-index) was used to assess the accuracy and reliability of the model. Results Of the 44,852 individuals at baseline, 2,912 were diagnosed with T2DM during the follow-up period, and the incidence density rate per 1,000 person-years was 16.00. Multivariate analysis indicated that male sex (P

Forkhead box O (FoxO), a key transcription factor in many species, participates in numerous physiological and pathological processes of organisms through a variety of signaling pathways. In the present study, we established DsFoxO knockout (DsFoxO-KO) strain using CRISPR/Cas9, and the influence on development and fecundity of mutant strain were evaluated. To clarify the corresponding mechanism, a transcriptome analysis was conducted subsequently. The results showed that the survival rates of the DsFoxO-KO strain in larval, pupal, and adult stages were all significantly lower than those of control. The duration of the pupal stage was similar between the two strains; however, durations of egg, larva, adult preoviposition period (APOP), and total APOP (TPOP) in the DsFoxO-KO strain were all significantly longer compared to those of the control strain. The fecundity of the DsFoxO-KO strain was 20.31 eggs/female, which was significantly lower than that of the control strain (430.47 eggs/female). With the transcriptome analysis, 612 differentially expressed genes (DEGs) were identified. Following COG and GO analyses, we found that most of the DEGs were associated with the metabolic process. According to the KEGG database, the mTOR signaling, MAPK signaling, Wnt signaling, and Toll and Imd signaling pathways; insect hormone biosynthesis; autophagy; and apoptosis were altered in the DsFoxO-KO strain. These results demonstrated that knockout of DsFoxO in D. suzukii significantly influenced its development and fecundity, while transcriptome analysis provided insights to explore the corresponding molecular mechanism. These findings highlighted the critical role of FoxO in D. suzukii and might contribute to the development of novel management strategies for these flies in the future.

Hydrodynamic cavitation (HC) is widely considered a promising process intensification technology. The novel advanced rotational hydrodynamic cavitation reactors (ARHCRs), with considerably higher performance compared with traditional devices, have gained increasing attention of academic and industrial communities. The cavitation generation unit (CGU), located on the rotor and/or stator of an ARHCR, is utilized to generate cavitation and consequently, its geometrical structure is vital for the performance. The present work studied, for the first time, the effect of the arrangement of CGU on the performance of a representative ARHCR by employing computational fluid dynamics based on the “simplified flow field” strategy. The effect of CGU arrangement, which was neglected in the past, was evaluated: radial offset distance (c), intersection angle (ω), number of rows (N), circumferential offset angle (γ), and radial spacing (r). The results indicate that the CGU, with an arrangement of a low ω and moderate c, N, γ, and r, performed the highest cavitation efficiency. The corresponding reasons were analyzed by combining the flow field and cavitation pattern. Moreover, the results also exposed a weakness of the “simplified flow field” strategy which may induce the unfavorable “sidewall effect” and cause false high-pressure region. The findings of this work may provide a reference value to the design of ARHCRs.

Osseointegration between biomaterial and bone is critical for the clinical success of many orthopaedic and dental implants. However, the mechanisms of in vivo interfacial bonding formation and the role of immune cells in this process remain unclear. In this study, we investigated the bone-scaffold material interfaces in two different 3D printed porous scaffolds (polymer/hydroxyapatite and sintered hydroxyapatite) that elicited different levels of foreign body response (FBR). The polymer/hydroxyapatite composite scaffolds elicited more intensive FBR, which was evidenced by more FBR components, such as macrophages/foreign body giant cells and fibrous tissue, surrounding the material surface. Sintered hydroxyapatite scaffolds showed less intensive FBR compared to the composite scaffolds. The interfacial bonding appeared to form via new bone first forming within the pores of the scaffolds followed by growing towards strut surfaces. In contrast, it was previously thought that bone regeneration starts at biomaterial surfaces via osteogenic stem/progenitor cells first attaching to them. The material-bone interface of the less immunogenic hydroxyapatite scaffolds was heterogenous across all samples, evidenced by the coexistence of osseointegration and FBR components. The presence of FBR components appeared to inhibit osseointegration. Where FBR components were present there was no osseointegration. Our results offer new insight on the in vivo formation of bone-material interface, which highlights the importance of minimizing FBR to facilitate osseointegration for the development of better orthopaedic and dental biomaterials.

Summary: LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has cured many patients with malignant hematologic diseases such as mixed phenotype acute leukemia (MPAL), while those relapsing after allo-HSCT still exhibit high mortality, poor prognosis, and no standard treatment modalities. It is necessary to explore more therapeutic modalities for patients with post-transplant relapse to obtain a better prognosis.Case presentationIn this case report, a young male with MPAL received allo-HSCT after reaching complete remission (CR) by induction chemotherapy. Unfortunately, relapse of both myeloid and T lineages occurred nine months later. After receiving demethylating chemotherapy, myeloid lineage measurable residual disease (MRD) turned negative. T-lineage MRD turned negative after CD7-targeted chimeric antigen receptor (CAR)-T cell therapy. The bone marrow remained MRD-negative for 4 months. This case preliminarily demonstrated a long-lasting CR with CD7-targeted CAR-T cell therapy, allowing a better prognosis.ConclusionDemethylating drugs combined with CD7-targeted CAR-T cell therapy is feasible in treating MPAL patients with relapse after transplantation, with good efficacy and safety, which will be a promising treatment option for MPAL.

Trialeurodes vaporariorum Westwood (greenhouse whitefly) are worldwide polyphagous pests of economic importance that damage solanaceous vegetables. Neonicotinoid pesticides and parasitoid Encarsia formmosa Gahan are the main management strategies applied worldwide, but precise control methods in greenhouse vegetables need to be developed to reduce the application amounts of pesticides and improve the suppression of whitefly populations. Therefore, we assessed the indoor acute toxicities and risk assessment of neonicotinoids for T. vaporariorum and E. formosa adults and pupae and compared the control effects of E. formosa and neonicotinoid acetamiprid. According to the acute toxicities results, most neonicotinoid insecticides were more toxic to E. formosa than T. vaporariorum, and pupae were much less susceptible than adults of both species. Moreover, acetamiprid had a low risk effect on E. formosa. Sole application of E. formosa and acetamiprid could effectively control T. vaporariorum, but their combined application resulted in antagonistic effects on the control of T. vaporariorum. The results showed that a combined application or sole use of E. formosa could reduce the use of insecticides, slow down the development of insecticide resistance in whiteflies, and improve the efficiency of controlling the growth of whitefly populations in greenhouse vegetable production.

Prohibited additives in infant formula severely affect the health of infants. Terahertz (THz) spectroscopy has enormous application potential in analyte detection due to its rich fingerprint information content. However, there is limited research on the mixtures of multiple analytes. In this study, we propose a split ring metasurface that supports magnetic dipole bound states in the continuum (BIC). By breaking the symmetry, quasi-BIC with a high quality (Q) factor can be generated. Utilizing an angle-scanning strategy, the frequency of the resonance dip can be shifted, resulting in the plotting of an envelope curve which can reflect the molecular fingerprint of the analytes. Two prohibited additives found in infant formula, melamine and vanillin, can be identified in different proportions. Furthermore, a metric similar to the resolution in chromatographic analysis is introduced and calculated to be 0.61, indicating that these two additives can be detected simultaneously. Our research provides a new solution for detecting additives in infant formula.

Coaxial rotor helicopters have great potential in civilian and commercial uses, with many advantages, but challenges remain in the accurate measurement of rotor blades’ distance to prevent blade collision. In this paper, a blade tip distance measurement method based on ultrasonic measurement window and phase triggering is proposed, and the triggering time of the transmitter is studied. Due to the complexity of the measured signal, bandpass filtering and a time-of-flight (TOF) estimation based on the power density of the received signal are utilised. The method is tested on an experimental test platform with a pair of 200 kHz ultrasonic transducers. The experimental results show that the maximum ranging error is less than 1.0% for the blade tip distance in a range of 100–1000 mm. Compared with the amplitude threshold method, the proposed TOF estimation method works well on the received signal with a low SNR and improves the ranging accuracy by about 5 mm when the blade tip distance is larger than 500 mm. This study provides a good reference for the accurate measurement of rotor blade tip distance, and gives a solution for ranging high-speed rotating objects.

Spectroscopy is a powerful tool to identify the specific fingerprints of analytes in a label-free way. However, conventional sensing methods face unavoidable barriers in analyzing trace-amount target molecules due to the difficulties of enhancing the broadband molecular absorption. Here, we propose a sensing scheme to achieve strong fingerprint absorption based on the angular-scanning strategy on an all-silicon metasurface. By integrating the mid-infrared and terahertz sensing units into a single metasurface, the sensor can efficiently identify 2,4-DNT with high sensitivity. The results reveal that the fingerprint peak in the enhanced fingerprint spectrum is formed by the linked envelope. It exhibits a significant enhancement factor exceeding 64-fold in the terahertz region and more than 55-fold in the mid-infrared region. Particularly, the corresponding identification limit of 2,4-DNT is 1.32 µg cm−2, respectively. Our study will provide a novel research idea in identifying trace-amount explosives and advance practical applications of absorption spectroscopy enhancement identification in civil and military security industries.