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Objectives: This study aimed to explore the effectiveness of the theory-based tailored mHealth physical activity (PA) intervention among patients with breast cancer undergoing chemotherapy. Methods: A quasi-experimental study design was adopted. A total of 60 breast cancer patients were selected from two tertiary hospitals in Shanghai and Hangzhou City from September 2019 to August 2021. According to the admission order, 30 patients were first included in the control group, followed by 30 patients in the intervention group. A smartphone application (app) named “Breast Care” was developed based on social cognitive theory, self-efficacy theory, and the theory of planned behavior. The app integrated various functions, including information browsing, PA monitoring and feedback, symptom reporting, and social interaction. Patients in the intervention group received three months of personalized online PA guidance in addition to routine care. The control group received routine care. Baseline and post-intervention investigations after three months were conducted in two groups using the Short Form of International Physical Activity Questionnaire, the Hospital Anxiety and Depression Scale, and the Functional Assessment of Cancer Therapy—Breast cancer. Results: After three months of intervention, compared to the control group, breast cancer patients in the intervention group showed significant improvements in walking, moderate PA, and overall PA (P

Abstract Background Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle. Results Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8+ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier. Conclusions Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses. Graphical Abstract

Abstract Cyclo[n]carbons have recently attracted significant attention owing to their geometric and electronic structures remaining largely unexplored in the condensed phase. In this work, we focus on two anti-aromatic cyclocarbons, namely C12 and C20. By designing two fully halogenated molecular precursors both including 4-numbered rings, we further extend the on-surface retro-Bergman ring-opening reaction, and successfully produce C12 and C20. The polyynic structures of C12 and C20 are unambiguously revealed by bond-resolved atomic force microscopy. More importantly, subtly positioning the C20 molecule into an atomic fence formed by Cl clusters allows us to experimentally probe its frontier molecular orbitals, yielding a transport gap of 3.8 eV measured from scanning tunneling spectroscopy. Our work may advance the field by easier synthesis of a series of cyclocarbons via on-surface retro-Bergman ring-opening strategy.

Abstract Background Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease. Methods In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone’s impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model. Results Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.

Abstract Background The health effects of Life’s Essential 8 (LE8) on chronic diseases have been disclosed, but its association with hypertension remains unknown. The current study aimed to explore the potential link between 10-year LE8 trajectory and the incidence of hypertension. Methods LE8 was constructed from four behaviors and four metabolic factors, ranging from 0 to 100. Latent mixture models were used to identify trajectories of LE8 scores during 2006 to 2016. Incident hypertension was diagnosed based on self-reported clinical diagnoses and physical examinations from 2016 to 2020. Cox models were employed to assess the association of LE8 trajectories with hypertension. In addition to incorporating the mean hs-CRP levels from 2006 to 2016, age, sex, monthly income, educational level, and occupation at recruitment were adjusted for as confounding factors. Results 7500 participants aged 40.28 ± 10.35 years were included in the study, of whom 2907 (38.76%) were women. Five LE8 trajectory patterns were identified. After around four-year follow-up, 667 hypertension events were observed. Compared to the Low-Stable trajectory, the hazard ratios and 95% confidence intervals for the Moderate-Increasing, Moderate-Decreasing, Moderate-Stable, and High-Stable trajectories were 0.51 (0.40, 0.65), 0.81 (0.64, 1.02), 0.45 (0.36, 0.58), 0.23 (0.16, 0.33), respectively. The risk of incident hypertension decreased as participants improved their LE8 status. The robustness of the primary results was confirmed through several sensitivity analyses. Conclusions LE8 trajectories were associated with the incident hypertension. People who improved their LE8 scores over time experienced a decreased risk of hypertension, even if they started with lower LE8 scores initially.

Objective The insufficient toe load of the fastener elastic rod will induce loosening of the surrounding fasteners, aggravate the dynamic response between wheels and rails, affecting the service life of the track components. Compared with the missing and breaking of the fastener elastic rod, fastener elastic rod loosening is more difficult to be spotted by routine manual inspection, so the toe load detection method of the fastener elastic rods needs to be studied. Method Taking WJ-7 fastener elastic rod of high-speed railway as an example, a refined model of fastener system is established, the modal characteristics of fastener elastic rod under different toe load states are analyzed, corresponding relationship between the toe load of fastener elastic rod and the natural frequency is obtained, and a rapid non-destructive testing method for calculating the toe load by testing the modal frequency of elastic rod is proposed accordingly. The high-speed railway line at the track test base of a State Key Laboratory is selected as the test site, and the test verification of the detection method is carried out. Result & Conclusion Under different toe load states, the 1st modal shape characteristics of elastic rods all manifest as vertical vibration and torsion on both side legs of the elastic rod. The maximum absolute value of the difference ratio between the simulation value and the measured value of the elastic rod 1st order natural frequency is 3.24%, so the test method can be considered as effective.

Abstract While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

Abstract Nitrous oxide (N2O) emissions are a serious global issue, with substantial evidence indicating that hydroclimate processes significantly contribute to these emissions. Forests, covering one-third of global land, are key in the water cycle and influence hydroclimate processes, which vary with climate, latitude, and forest types. The role of hydroclimate in regulating global forest N2O emission remains largely unknown. Our global analysis shows that hydroclimate factors dominate the latitudinal gradient of forest N2O fluxes, which decrease with latitude. N2O fluxes are highest in tropical forests, followed by temperate and boreal forests. Hydroclimate factors contribute 78.2% to N2O fluxes, while soil factors contribute 21.8%. Our results urgently call for future studies to investigate the relationship between N2O flux and hydroclimate factors like radiation, evapotranspiration, and vapor pressure deficits. Collectively, these findings highlight hydroclimate significant impact on N2O emissions and suggest incorporating these factors into predictive models for greater accuracy.

Abstract β-Lactam antibiotics are a class of antibiotics commonly used to treat bacterial infections. However, the effects of β-lactam antibiotics on term neonatal intestinal flora have not been fully elucidated. Hospitalized full-term newborns receiving β-lactam antibiotics formed the antibiotic group (n = 67), while those without antibiotic treatment comprised the non-antibiotic group (n = 47). A healthy group included healthy full-term newborns (n = 16). Stool samples were collected for 16 S rDNA sequencing to analyze gut microbiota variations. Further investigation was carried out within the β-lactam antibiotic group, exploring the effects of antibiotic use on the newborns’ gut microbiota in relation to the duration and type of antibiotic administration, delivery method, and feeding practices. The antibiotic group exhibited significant difference of microbial community composition compared to the other groups. Genera like Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas were enriched, while Escherichia-Shigella, Clostridium sensu stricto 1, Bifidobacterium, and Parabacteroides were reduced. Klebsiella negatively correlated with Escherichia-Shigella, positively with Enterobacter, while Escherichia-Shigella negatively correlated with Enterococcus and Streptococcus. Regardless of neonatal age, β-lactam antibiotics induced an elevated abundance of Klebsiella and Enterococcus. The impact on gut microbiota varied with the duration and type of antibiotic (cefotaxime or ampicillin/sulbactam). Compared to vaginal delivery, cesarean delivery after β-lactam treatment heightened the abundance of Klebsiella, Enterobacteriaceae_Unclassified, Lactobacillales_Unclassified, and Pectobacterium. Feeding patterns minimally influenced β-lactam-induced alterations. In conclusion, β-lactam antibiotic treatment for neonatal pneumonia and sepsis markedly disrupted intestinal microbiota, favoring Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas. The impact of β-lactam varied by duration, type, and delivery method, emphasizing heightened disruptions post-cesarean delivery.

Abstract There is insufficient evidence to guide dose and frequency optimization with repeated-dose ketamine for depression. This study assessed the value of symptomatic non-improvement after the first few ketamine infusions as a predictor of overall non-response in depression for early decision-making to discontinue treatment. A total of 135 individuals with major depressive disorder or bipolar disorder experiencing a current major depressive episode were administered six repeated doses of intravenous ketamine. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, 4 h after the first infusion, and 24 h after each infusion. Improvement, partial response, and response were defined as a reduction rate of ≥ 20%, 30%, and 50% in MADRS scores, respectively. This study examined the relationship between improvement (as opposed to non-improvement after each infusion or consecutive non-improvements after the first few infusions) and partial response and response after the sixth infusion. This analysis was summarized using sensitivity, specificity, and other diagnostic test parameters. The sensitivities of improvement at 24 h post-infusion 4 and improvement at 24 h post-infusion 3, vs. three consecutive non-improvements, as predictors for overall partial response and response exceeded 90%. No significant reduction in depressive symptoms was seen in non-improvers following the remaining infusions after the above-identified point. Our study suggests that non-improvement after four infusions, or more conservatively three consecutive non-improvements after three infusions, could serve as a signal of overall non-response to repeated-dose intravenous ketamine for depression and that subsequent treatments would not be warranted.

Abstract Non-iatrogenic trauma of the iliac artery is rarely reported but is always life-threatening. In this report, we describe the case of a child with complete transection and partial disappearance of the iliac artery caused by bicycle handlebar impalement. He experienced catastrophic hemorrhage, malignant arrhythmia, and difficulty in exploring transected vessel stumps. Aggressive infusion, blood transfusion in time, and pediatric vascular characteristics help delay the deterioration during anesthesia induction. Eventually he was successfully rescued by performing interventional balloon occlusion and open revascularization after more than 7 h post-trauma. A series of interventions and precautionary methods may benefit such severely injured patients; thus, these methods should be highlighted.

Abstract The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P

Abstract Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid cancer with poor prognosis. Killing cancer cells by inducing DNA damage or blockage of DNA repair is a promising strategy for chemotherapy. It is reported that aldehyde-reactive alkoxyamines can capture the AP sites, one of the most common DNA lesions, and inhibit apurinic/apyrimidinic endonuclease 1(APE1)-mediated base excision repair (BER), leading to cell death. Whether this strategy can be employed for ATC treatment is rarely investigated. The aim of this study is to exploit GSH-responsive AP site capture reagent (AP probe-net), which responses to the elevated glutathione (GSH) levels in the tumor micro-environment (TME), releasing reactive alkoxyamine to trap AP sites and block the APE1-mediated BER for targeted anti-tumor activity against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrate their selective cytotoxicity towards ATC cells over normal thyroid cells. Flow cytometry analysis suggests that AP probe-net arrests the cell cycle in the G2/M phase and induces apoptosis. Western blotting (WB) results show that the expression of apoptotic protein increased with the increased concentration of AP probe-net. Further in vivo experiments reveal that the AP probe-net has a good therapeutic effect on subcutaneous tumors of the ATC cells. In conclusion, taking advantage of the elevated GSH in TME, our study affords a new strategy for targeted chemotherapy of ATC with high selectivity and reduced adverse effects.

In order to reduce the enzymatic browning of loquat pulp during the pulping process and to maintain the original color of the pulp, the color difference value (ΔE) was used as the main response variable. The effect of six color protectors in protecting loquat pulp from pulping was investigated and the two best performers were selected for the central composite design (CCD) test. Based on this, an investigation was conducted into the effect of composite color protection on the color and the content of nutrition of loquat pulp during storage at 5 ℃ for 28 days. Out of the six color protectors, the results indicated that ascorbic acid and phytic acid had a significant impact on color protection, and the optimal ratio included 0.332% ascorbic acid, 0.065% phytic acid. The verification test showed the average ΔE of loquat pulp after composite color protection was 6.70, which closely aligned with the predicted value at 97.31% agreement. The storage test showed that the composite color protection could effectively retard the decrease in L*, a*, b* and ΔE values of loquat pulp, while reducing the loss of total sugar, ascorbic acid and total phenol, and the increased of titratable acid content, to maintain the nutrition of the pulp. This study could provide technical reference for the processing and utilization of loquat.

This study reports the preparation of two single-phase high-entropy rare-earth niobates (RE1/5Ho1/5Er1/5Y1/5Yb1/5)3NbO7, (RE = Ce, Lu), and two composite-phase high-entropy rare-earth niobates (RE1/5Ho1/5Er1/5Y1/5Yb1/5)3NbO7:(RE1/5Ho1/5Er1/5Y1/5Yb1/5)NbO4 = 1:2, (RE = Ce, Lu) via solid-phase synthesis. The interactions of these samples with molten calcium-magnesium-aluminum-silicates (CMAS) were studied at 1300 °C to explore their performance and mechanism in CMAS corrosion. The results indicate that the corrosion process involves the phase transformation of RE3NbO7 and the formation of apatite products. The Ce-composition sample exhibits superior performance in terms of reaction layer thickness, remaining CMAS thickness, and RE3+ content in the remaining CMAS. These findings underscore the potential application of high-entropy rare-earth niobates in thermal barrier coatings (TBCs) and contribute to understanding niobate system resistance to CMAS corrosion.

ABSTRACTThe rising prevalence and detrimental impact of inflammatory diseases have spurred the exploration of novel therapeutic approaches to tackle these conditions. Fuzi, lateral root of Aconitum carmichaelii Debx. has been used as a traditional Chinese medicine (TCM) for the treatment of inflammatory diseases for a long time. This article provides a comprehensive review of the medicinal applications, anti-inflammatory constituents, analytical techniques for detecting anti-inflammatory components, molecular mechanisms, and anti-inflammatory effects of Fuzi and its formulas. The information on Fuzi was collected from a variety of resources including classical works on Chinese herbal medicine, scientific databases (PubMed, Google Scholar, ACS, Web of Science, Science Direct, CNKI), TCMSP, NCBI, PubChem databases and others. About 122 compounds were isolated and identified from Fuzi, with alkaloids constituting the primary constituents that demonstrate potent anti-inflammatory activity. Specifically, among the identified compounds, there was one C-18 type, nineteen C-19 type, four C-20 type diterpenoid alkaloids, one other alkaloid, and 6 non-alkaloid constituents, all of which exhibited noteworthy anti-inflammatory and pain-alleviating properties in both in vivo and in vitro models of inflammation. These effects were mainly attributed to the reduction of pro-inflammatory cytokines, including IL-1, TNF-α, NO, IL-Iβ, and IL-6, as well as the inhibition of MAPK, NF-κB or PI3K/Akt signaling pathways, which effectively suppressed the inflammatory response and alleviated pain. Additionally, the anti-inflammatory effects were also achieved through the regulation of TLR4 expression and its downstream factors, or by modulating the homeostasis of the gut microbiota.

In this research, a novel method for regulating components in RE2SiO5/RE2Si2O7 multiphase silicates was developed, combining the benefits of a suitable thermal expansion coefficient (CTE) and outstanding corrosion resistance against calcium–magnesium–alumino–silicate (CMAS). This approach enhanced the overall thermophysical properties. Additionally, the results from the CMAS corrosion resistance test indicated that (Lu1/3Yb1/3Tm1/3)2SiO5/(Lu1/3Yb1/3Tm1/3)2Si2O7 and (Lu1/4Yb1/4Tm1/4Er1/4)2SiO5/(Lu1/4Yb1/4Tm1/4Er1/4)2Si2O7 exhibited exceptional resistance to CMAS penetration, even at temperatures up to 1500 °C. To comprehend the corrosion mechanism of CMAS on these silicates, we introduced a reaction–diffusion model, which involved observing the changes in the interface between the corrosion product layer and the silicate block. This was achieved using electron backscatter diffraction (EBSD). These findings lay a theoretical basis for selecting rare earth elements in RE2SiO5/RE2Si2O7 multiphase silicates based on the radii of different rare earth cations.

Abstract Background Chicken coccidiosis is a protozoan disease that leads to considerable economic losses in the poultry industry. Live oocyst vaccination is currently the most effective measure for the prevention of coccidiosis. However, it provides limited protection with several drawbacks, such as poor immunological protection and potential reversion to virulence. Therefore, the development of effective and safe vaccines against chicken coccidiosis is still urgently needed. Methods In this study, a novel oral vaccine against Eimeria tenella was developed by constructing a recombinant Lactobacillus plantarum (NC8) strain expressing the E. tenella RON2 protein. We administered recombinant L. plantarum orally at 3, 4 and 5 days of age and again at 17, 18 and 19 days of age. Meanwhile, each chick in the commercial vaccine group was immunized with 3 × 102 live oocysts of coccidia. A total of 5 × 104 sporulated oocysts of E. tenella were inoculated in each chicken at 30 days. Then, the immunoprotection effect was evaluated after E. tenella infection. Results The results showed that the proportion of CD4+ and CD8+ T cells, the proliferative ability of spleen lymphocytes, inflammatory cytokine levels and specific antibody titers of chicks immunized with recombinant L. plantarum were significantly increased (P

TikTok has become a hub for easily accessible medical information. However, the quality and completeness of this information for testicular cancer has not been examined. Our study aims to assess the quality and completeness of testicular cancer information on TikTok. A search was performed on TikTok using the search terms “Testicular Cancer” and “Testicle Cancer”. Inclusion criteria encompassed videos about testicular cancer in English. We excluded non-English videos, irrelevant videos, and videos without audio. We evaluated these videos using the DISCERN instrument and a completeness assessment. A total of 361 videos were considered for screening and 116 videos were included. Of these, 57 were created by healthcare professionals (HCPs). The median video length was 40 s (5–277 s), with >25 million cumulative views and a median of 446,400 views per video. The average DISCERN score was 29.0 ± 5.7, with HCPs providing higher-quality videos than non-HCPs (30.8 vs. 5.5, p < 0.05). HCPs also had more reliable videos (21.2 vs. 18.1, p < 0.05). Overall quality levels were mostly poor or very poor (97.4%), with none being good or excellent. Most HCP videos were poor (63.2%), whilst many non-HCP videos were very poor (61.0%). The most viewed video had 2,800,000 views but scored a 31 on the DISCERN tool and one on the completeness assessment. The highest DISCERN score had 11,700 views. HCP videos better defined the disease and were more complete (p < 0.05). Most videos discussed self-assessment but were lacking in definitions, risk factors, symptoms, evaluation, management, and outcomes. Most of TikTok’s testicular cancer information lacks quality and completeness, whilst higher-quality videos have limited reach.

Abstract Objective To investigate the association between meteorological data three days before admission and the status of sputum pathogens culture in hospitalized patients with Acute exacerbation of Chronic obstructive pulmonary disease (AECOPD) and respiratory infections. Methods Data from 1,370 AECOPD patients (80.66% males, approximately 80% age > 70) with respiratory infections hospitalized in Fujian Provincial Hospital between December 2013 and December 2019 were collected. This cohort comprised, along with concurrent meteorological data from Fuzhou. Group differences were analyzed to compare the meteorological data three days prior to admission between patients with positive sputum pathogen cultures and those without. Logistic regression models were employed to investigate the association between meteorological parameters and the status of sputum pathogen cultures in patients with AECOPD and respiratory infections. Sensitivity analyses was conducted among the hospitalized patients from 2013 to 2016 and 2017–2019. Stratified analysis was performed to explore the factors affecting the effect of temperature differences and their interactions. Results 578(42.19%) cases had a positive sputum culture report indicating pathogen growth. 323 cases were found with Gram-negative bacteria, 160 with Gram-positive bacteria, and 114 with fungi. Uni-variate analysis revealed statistical differences in DTD three days prior to admission (DTD-3d) between the positive and negative sputum culture groups (p = 0.019). Multivariate analysis indicated that an increase in the risk of positive sputum pathogen cultures was associated with greater DTD three days before admission (DTD-3d), with OR1.657 (95%CI [ 1.328–1.981]). The risk of positive sputum pathogen cultures was higher in groups with greater DTD-3d. The findings were consistent across different admission periods. Stratified analysis showed that patients without respiratory failure were more affected by DTD-3d, and an interaction effect was observed (p

Abstract Background Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). Methods The SCCS is a prospective cohort of primarily low-income adults aged 40–79, enrolled from the southeastern United States during 2002–2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. Results Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P

[Introduction] Plasma disruption poses a significant threat to the tokamak nuclear device during its running and can cause damage to the device. Such damage can be reduced by adopting the disruption mitigation system, which has an action time highly dependent on the real-time running plasma disruption prediction system for predicting the plasma disruption moment. The deep-learning-based neural network has been used to train plasma disruption prediction models, and the real-time running of the deep-learning-based disruption prediction models requires a huge amount of real-time data from multiple diagnostics. [Method] The article proposed a design scheme for a real-time data acquisition system. The real-time data acquisition and transmission system was designed based on the modular structure and divided into the multiple channels acquisition module, ADC converting control and data reading module, data grouping and packing module and data transmission network module. The data transmission network module was developed on the hardware UDP network stack running on the FPGA at a speed of 10 G. This hardware UDP network stack featured a deterministic data transmission process, enabling a very low transmission latency of the system. [Result] The real-time data acquisition system has a sampling rate reaching 2 MSa/s, a data throughput rate exceeding 9.3 Gb/s, and a data transmission latency of less than 10 μs. [Conclusion] This data acquisition system facilitates the fast transmission of diagnostic data streams to disruption prediction models. The high sampling rates enable the system to perform real-time transmission of one-dimensional diagnostics such as radiation and electron temperature, improving the temporal resolution of data. The high data throughput rate can increase the transmission volume of diagnostic data, and the low data transmission latency can reduce the time required for disruption prediction models to obtain diagnostics data.

Abstract Background The prevalence of hypertensive heart disease (HHD) is high and there is currently no easy way to detect early HHD. Explore the application of radiomics using cardiac magnetic resonance (CMR) non-enhanced cine sequences in diagnosing HHD and latent cardiac changes caused by hypertension. Methods 132 patients who underwent CMR scanning were divided into groups: HHD (42), hypertension with normal cardiac structure and function (HWN) group (46), and normal control (NOR) group (44). Myocardial regions of the end-diastolic (ED) and end-systolic (ES) phases of the CMR short-axis cine sequence images were segmented into regions of interest (ROI). Three feature subsets (ED, ES, and ED combined with ES) were established after radiomic least absolute shrinkage and selection operator feature selection. Nine radiomic models were built using random forest (RF), support vector machine (SVM), and naive Bayes. Model performance was analyzed using receiver operating characteristic curves, and metrics like accuracy, area under the curve (AUC), precision, recall, and specificity. Results The feature subsets included first-order, shape, and texture features. SVM of ED combined with ES achieved the highest accuracy (0.833), with a macro-average AUC of 0.941. AUCs for HHD, HWN, and NOR identification were 0.967, 0.876, and 0.963, respectively. Precisions were 0.972, 0.740, and 0.826; recalls were 0.833, 0.804, and 0.863, respectively; and specificities were 0.989, 0.863, and 0.909, respectively. Conclusions Radiomics technology using CMR non-enhanced cine sequences can detect early cardiac changes due to hypertension. It holds promise for future use in screening for latent cardiac damage in early HHD.

Abstract African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3′ UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P

Abstract Background Prime editing enables precise base substitutions, insertions, and deletions at targeted sites without the involvement of double-strand DNA breaks or exogenous donor DNA templates. However, the large size of prime editors (PEs) hampers their delivery in vivo via adeno-associated virus (AAV) due to the viral packaging limit. Previously reported split PE versions provide a size reduction, but they require intricate engineering and potentially compromise editing efficiency. Results Herein, we present a simplified split PE named as CC-PE, created through non-covalent recruitment of reverse transcriptase to the Cas9 nickase via coiled-coil heterodimers, which are widely used in protein design due to their modularity and well-understood sequence-structure relationship. We demonstrate that the CC-PE maintains or even surpasses the efficiency of unsplit PE in installing intended edits, with no increase in the levels of undesired byproducts within tested loci amongst a variety of cell types (HEK293T, A549, HCT116, and U2OS). Furthermore, coiled-coil heterodimers are used to engineer SpCas9-NG-PE and SpRY-PE, two Cas9 variants with more flexible editing scope. Similarly, the resulting NG-CC-PE and SpRY-CC-PE also achieve equivalent or enhanced efficiency of precise editing compared to the intact PE. When the dual AAV vectors carrying CC-PE are delivered into mice to target the Pcsk9 gene in the liver, CC-PE enables highly efficient precise editing, resulting in a significant reduction of plasma low-density lipoprotein cholesterol and total cholesterol. Conclusions Our innovative, modular system enhances flexibility, thus potentially facilitating the in vivo applicability of prime editing.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Abstract Research background and purpose Osteoporosis (OP) is one of the most common bone diseases worldwide, characterized by low bone mineral density and susceptibility to pathological fractures, especially in postmenopausal women and elderly men. Ferroptosis is one of the newly discovered forms of cell death regulated by genes in recent years. Many studies have shown that ferroptosis is closely related to many diseases. However, there are few studies on ferroptosis in osteoporosis, and the mechanism of ferroptosis in osteoporosis is still unclear. This study aims to identify biomarkers related to osteoporosis ferroptosis from the GEO (Gene Expression Omnibus) database through bioinformatics technology, and to mine potential therapeutic small molecule compounds through molecular docking technology, trying to provide a basis for the diagnosis and treatment of osteoporosis in the future. Materials and methods We downloaded the ferroptosis-related gene set from the FerrDb database ( http://www.zhounan.org/ferrdb/index.html ), downloaded the data sets GSE56815 and GSE7429 from the GEO database, and used the R software “limma” package to screen differentially expressed genes (DEGs) from GSE56815, and intersected with the ferroptosis gene set to obtain ferroptosis-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the R software “clusterProfiler” package. The random forest model was further screened to obtain essential ferroptosis genes. R software “corrplot” package was used for correlation analysis of essential ferroptosis genes, and the Wilcox test was used for significance analysis. The lncRNA-miRNA-mRNA-TF regulatory network was constructed using Cytoscape software. The least absolute shrinkage and selection operator (LASSO) was used to construct a disease diagnosis model, and a Receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic performance, and then GSE7429 was used to verify the reliability of the diagnosis model. Molecular docking technology was used to screen potential small molecule compounds from the Drugbank database. Finally, a rat osteoporosis model was constructed, and peripheral blood mononuclear cells were extracted for qRT-PCR detection to verify the mRNA expression levels of crucial ferroptosis genes. Result Six DEGs related to ferroptosis were initially screened out. GO function and KEGG pathway enrichment analysis showed that ferroptosis-related DEGs were mainly enriched in signaling pathways such as maintenance of iron ion homeostasis, copper ion binding function, and ferroptosis. The random forest model identified five key ferroptosis genes, including CP, FLT3, HAMP, HMOX1, and SLC2A3. Gene correlation analysis found a relatively low correlation between these five key ferroptosis genes. The lncRNA-miRNA-mRNA-TF regulatory network shows that BAZ1B and STAT3 may also be potential molecules. The ROC curve of the disease diagnosis model shows that the model has a good diagnostic performance. Molecular docking technology screened out three small molecule compounds, including NADH, Midostaurin, and Nintedanib small molecule compounds. qRT-PCR detection confirmed the differential expression of CP, FLT3, HAMP, HMOX1 and SLC2A3 between OP and normal control group. Conclusion This study identified five key ferroptosis genes (CP, FLT3, HAMP, HMOX1, and SLC2A3), they were most likely related to OP ferroptosis. In addition, we found that the small molecule compounds of NADH, Midostaurin, and Nintedanib had good docking scores with these five key ferroptosis genes. These findings may provide new clues for the early diagnosis and treatment of osteoporosis in the future.

Abstract Background Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles. Methods A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS. Results Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P

Abstract Background Dietary imbalance, such as a lower proportion of complex carbohydrates and a higher protein diet, may contribute to gestational diabetes mellitus (GDM) risks through their metabolisms. However, there is a lack of knowledge regarding the association between butyrate, iso-butyrate, and GDM, which are metabolisms of the two primary nutrients above. This study aimed to clarify the association of butyrate and iso-butyrate with GDM. Methods A nested case–control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2017 to 2018. Totally, 99 singleton women were involved (GDM: n = 49, control: n = 50). All participants provided blood samples twice (in their first and second trimesters). Gas chromatography-mass spectrometry (GC-MS) was used for butyrate and iso-butyrate detection. Unconditional logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. Results The results showed that butyrate in the first trimester was negatively correlated with GDM (odds ratio (OR): 0.00, 95% confidential interval (CI): 0.00–0.21, P = 0.008), and iso-butyrate in the second trimester was positively related to GDM (OR: 627.68, 95% CI: 40.51–9724.56, P

Abstract ‘Not in My Back Yard (NIMBY)’ facilities are psychologically sensitive to urban and regional development. Multi-criteria evaluation (MCE) method has been widely used for the decision-making of optimum siting of urban NIMBY facilities which aim to improve residents’ psychological satisfaction. However, the evaluation of qualitative criteria in siting analysis remains under researched, such as the insufficient focus on urban and regional spatial development, social public opinion, and psychological factors. Thus, the effective improvement of MCE method through an interdisciplinary view can optimise the decision process and advance the factor assessment system of siting, which helps to supplement qualitative criteria evaluation. The specific improvement steps are as follows. The first step is to introduce the mixed MCE method to improve the qualitative criteria evaluation method by pre-processing qualitative criteria with min–max standardisation and normalization. This process transfers all negative factors to positive ones and transforms the F function to linear functions. The second step is to optimise the existing two-phase siting decision-making including the feasibility evaluation phase and the MCE phase. The third step is to propose a modular criteria system composed of urban and regional spatial planning, social psychological factors and the corresponding improvement strategy of this system from three perspectives of composition, measure, and weight. We argue that the improved method could be broadly applied to optimum siting decision of urban NIMBY facilities and enhance the psychological satisfaction of residents.

Abstract It is difficult to obtain a single-phase environmental barrier coating material that simultaneously offers the advantages of low thermal conductivity, a suitable coefficient of thermal expansion, and excellent corrosion resistance. Herein, to synthesize the advantages of single-phase materials, we have developed an effective approach for the design of high-entropy multiphase ceramics of rare earth oxides and silicates. Such a specific design approach is capable of making high-entropy RE2SiO5/RE2O3 and RE2SiO5/RE2Si2O7 (RE = Lu, Yb, Tm, Er, Ho, and Y) multiphase ceramics as two types of potential environmental barrier coating materials for Al2O3f/Al2O3 and SiCf/SiC ceramic matrix composites.

Abstract Objective The objective was to assess the efficacy and safety of low-dose aspirin for the prevention of preterm birth in nulliparous women. Data sources We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to June 2022. Study eligibility criteria Randomized controlled trials that compared aspirin to placebo in nulliparous women were eligible. Methods This study was reported in accordance with the PRISMA 2020 checklist. The primary outcomes of this study were the rates of preterm birth at less than 37 weeks and less than 34 weeks of gestation. The secondary outcomes included postpartum hemorrhage, placental abruption, cesarean section, any hypertensive disorder of pregnancy and small for gestational age. Relative risks with their 95% confidence intervals were calculated for analysis. Heterogeneity was assessed by Cochran’s Q test and Higgins’s I2. A random-effects model was used when I2 was > 50% to generate the RR and 95% CI; otherwise, a fixed-effects model was used. The risk of publication bias was assessed by funnel plots. We performed sensitivity analysis by sequentially omitting each included study to confirm the robustness of the analysis. Results Seven studies with a total of 29,029 participants were included in this review. Six studies were assessed as having a low risk of bias or an unclear risk of bias, and one study was judged as having a high risk of bias. In nulliparous women, low-dose aspirin was associated with a significant reduction in the rate of preterm birth at less than 34 weeks of gestational age (RR 0.84,95% CI: 0.71–0.99; I2 = 0%; P = 0.04), but we did not observe a significant difference in the rate of preterm birth at less than 37 weeks of gestation (RR 0.96,95% CI: 0.90–1.02; I2 = 31%; P = 0.18). Low-dose aspirin was associated with a significant increase in the rates of postpartum hemorrhage (RR 1.32,95% CI: 1.14–1.54; I2 = 0%; P = 0.0003), placental abruption (RR 2.18,95% CI: 1.10–4.32; I2 = 16%; P = 0.02) and cesarean section (RR 1.053, 95% CI: 1.001–1.108; I2 = 0%; P = 0.05) in nulliparous women. We also did not observe a significant effect of low-dose aspirin on the rates of any hypertensive disorder of pregnancy (RR 1.05, 95% CI: 0.96–1.14; I2 = 9%; P = 0.28) or small for gestational age (RR 0.96, 95% CI: 0.91–1.02; I2 = 0%; P = 0.16) in nulliparous women. Funnel plots indicated that no significant publication bias existed in this meta-analysis. Except for preterm birth at less than 34 weeks of gestation, placental abruption and cesarean section, the sensitivity analysis showed similar results, which confirmed the robustness of this meta-analysis. Conclusions Low-dose aspirin might reduce the risk of preterm birth at less than 34 weeks of gestation in nulliparous women. The use of low-dose aspirin in nulliparous women increased the risk of postpartum hemorrhage and might increase the risk of placental abruption and cesarean section.

ObjectivesThe purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the effectiveness, safety, and tolerability of psilocybin in adult patients with major depressive disorder (MDD).MethodsA systematic search (up to September 14, 2023) was conducted for RCTs that examined the efficacy, safety, and tolerability of psilocybin in physically healthy adult patients with MDD. Three independent researchers extracted data from publications where the primary outcome was a change in depressive symptoms, and key secondary outcomes were changes in anxiety symptoms and suicidal ideation, discontinuation rates for any reason, and adverse drug reactions (ADRs).ResultsFive RCTs with 472 adult patients with MDD on psilocybin (n = 274) and controls (n = 198) were included. Two of the five RCTs (40%) reported mixed results, while the other three (60%) found that psilocybin had a beneficial effect on MDD treatment. Four RCTs (80%) assessing the anxiolytic effects of psilocybin for treating MDD found that psilocybin was significantly more effective than the control group in improving anxiety symptoms. Psilocybin was more effective than the control group in improving suicidal ideation in one out of five RCTs. Discontinuation rates were similar for any reason between the psilocybin group (2–13%) and the control group (4–21%) (P > 0.05). Four RCTs (80%) reported ADRs in detail. The most common ADR in both groups was headache.ConclusionPsilocybin was effective in improving depressive symptoms in over half of the included studies and reduced anxiety symptoms in patients with MDD. The long-term efficacy and safety of psilocybin for MDD treatment needs to be further investigated in large RCTs.

IntroductionIn recent years, nitrogen deposition has constantly continued to rise globally. However, the impact of nitrogen deposition on the soil physicochemical properties and microbial community structure in northern Guangxi is still unclear.MethodsAlong these lines, in this work, to investigate the impact of atmospheric nitrogen deposition on soil nutrient status and bacterial community in subtropical regions, four different nitrogen treatments (CK: 0 gN m–2 a–1, II: 50 gN m–2 a–1, III: 100 gN m–2 a–1, IV: 150 gNm– 2 a–1) were established. The focus was on analyzing the soil physical and chemical properties, as well as bacterial community characteristics across varying nitrogen application levels.Results and discussionFrom the acquired results, it was demonstrated that nitrogen application led to a significant decrease in soil pH. Compared with CK, the pH of treatment IV decreased by 4.23%, which corresponded to an increase in soil organic carbon and total nitrogen. Moreover, compared with CK, the soil organic carbon of treatment IV increased by 9.28%, and the total nitrogen of treatment IV increased by 19.69%. However, no significant impact on the available nitrogen and phosphorus was detected. The bacterial diversity index first increased and then decreased with the increase of the nitrogen application level. The dominant phylum in the soil was Acidobacteria (34.63–40.67%), Proteobacteria, and Chloroflexi. Interestingly, the abundance of Acidobacteria notably increased with higher nitrogen application levels, particularly evident in the IV treatment group where it surpassed the control group. Considering that nitrogen addition first changes soil nutrients and then lowers soil pH, the abundance of certain oligotrophic bacteria like Acidobacteria can be caused, which showed a first decreasing and then increasing trend. On the contrary, eutrophic bacteria, such as Actinobacteria and Proteobacteria, displayed a decline. From the redundancy analysis, it was highlighted that total nitrogen and pH were the primary driving forces affecting the bacterial community composition.

As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA.

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1G93A or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1G93A mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1G93A mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1G93A mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.

Power transformer plays a critical role in grid infrastructure, and its diagnosis is paramount for maintaining stable operation. However, the current methods for transformer diagnosis focus on discrete dissolved gas analysis, neglecting deep feature extraction of multichannel consecutive data. The unutilized sequential data contains the significant temporal information reflecting the transformer condition. In light of this, the structure of multichannel consecutive data cross-extraction (MCDC) is proposed in this article in order to comprehensively exploit the intrinsic characteristic and evaluate the states of transformer. Moreover, for the better accommodation in scenario of transformer diagnosis, one dimensional convolution neural network attention (1DCNN-attention) mechanism is introduced and offers a more efficient solution given the simplified spatial complexity. Finally, the effectiveness of MCDC and the superior generalization ability, compared with other algorithms, are validated in experiments conducted on a dataset collected from real operation cases of power transformer. Additionally, the better stability of 1DCNN-attention has also been certified.

Abstract For decreasing the global cost of corrosion, it is essential to understand the intricate mechanisms of corrosion and enhance the corrosion resistance of materials. However, the ambiguity surrounding the dominant mechanism of calcium‐magnesium aluminosilicate (CMAS) molten salt corrosion in extreme environments hinders the mix‐and‐matching of the key rare earth elements for increasing the resistance of monosilicates against corrosion of CMAS. Herein, an approach based on correlated electron microscopy techniques combined with density functional theory calculations is presented to elucidate the complex interplay of competing mechanisms that control the corrosion of CMAS of monosilicates. These findings reveal a competition between thermodynamics and kinetics that relies on the temperatures and corrosion processes. Innovative medium‐entropy monosilicates with exceptional corrosion resistance even at 1500 °C are developed. This is achieved by precisely modulating the radii of rare earth ions in monosilicates to strike a delicate balance between the competition in thermodynamics and kinetics. After 50 and 100 h of corrosion, the thinnest reactive layers are measured to be only 28.8 and 35.4 µm, respectively.

ABSTRACT The pharmacological activation of peroxisome proliferator‐activated receptor gamma (PPARγ) is a convenient and promising strategy for promoting beige adipocyte biogenesis to combat obesity‐related metabolic disorders. However, thiazolidinediones (TZDs), the full agonists of PPARγ exhibit severe side effects in animal models and in clinical settings. Therefore, the development of efficient and safe PPARγ modulators for the treatment of metabolic diseases is emerging. In this study, using comprehensive methods, we report a previously unidentified ligand‐binding pocket (LBP) in PPARγ and link it to beige adipocyte differentiation. Further virtual screening of 4097 natural compounds based on this novel LBP revealed that saikosaponin A (NJT‐2), a terpenoid compound, can bind to PPARγ to induce coactivator recruitment and effectively activate PPARγ‐mediated transcription of the beige adipocyte program. In a mouse model, NJT‐2 administration efficiently promoted beige adipocyte biogenesis and improved obesity‐associated metabolic dysfunction, with significantly fewer adverse effects than those observed with TZD. Our results not only provide an advanced molecular insight into the structural ligand‐binding details in PPARγ, but also develop a linked selective and safe agonist for obesity treatment.

ObjectivesGenetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.MethodsThe analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.ResultsIn our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.ConclusionOur investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.

ObjectiveThis study aims to examine the alterations in aberrant brain activity and network connectivity between individuals with mild and major vascular cognitive impairment (VCI).Materials and methodsA total of 114 patients with cerebral small vessel disease (CSVD) were included in this study, comprising 61 individuals with mild VCI (mean age, 55.7 ± 6.9 years; male, 42.6%) and 53 cases with major VCI (mean age, 57.6 ± 5.5 years; male, 58.5%). Additionally, 53 age-, gender-, and education-matched healthy subjects were recruited as normal controls (NC) (mean age, 54.9 ± 7.9 years; male, 52.9%). All participants underwent neuropsychological assessments and magnetic resonance imaging scans. One-way analysis of variance was used to compare fractional amplitude of low-frequency fluctuation (fALFF) values among the three groups. Two-sample t-tests were conducted to assess functional connectivity matrices between different groups for each connection. Moreover, mediation analyses were performed to explore the mediating effect of aberrant brain activity on the relationship between cognitive impairment and CSVD total burden.ResultsVCI patients exhibited aberrant brain activity in regions such as the right thalamus (THA_R), right cuneus (CUN_R), left postcentral gyrus (PoCG_L), right postcentral gyrus (PoCG_R), right median cingulate, paracingulate gyri (PCG_R), and left precuneus (PCUN_L). Reduced positive functional connectivity was predominantly observed among nodes including PCUN_L, CUN_R, PoCG_L, PoCG_R, right posterior cingulate (PCG_R), and left occipital gyrus (IOG_L) in VCI patients. The aberrant baseline brain activity and disrupted brain network were more pronounced with worsening cognitive function. Increased fALFF values in THA_R, CUN_R, and PoCG_L mediated cognitive impairment in CSVD patients.ConclusionAbnormal brain activities in THA_R, CUN_R, and PoCG_L, along with their associated abnormal functional connections, play a significant role in VCI. The study revealed a progressive increase in aberrant brain activity and network connectivity with advancing stages of VCI.

Abstract Lung cancer remains the leading cause of cancer mortality worldwide. Small cell lung cancer (SCLC) accounts for 10–15% of cases and has an overall 5-years survival rate of only 15%. Neuron-specific enolase (NSE) has been identified as a useful biomarker for early SCLC diagnosis and therapeutic monitoring. This work reports an electrochemical immunosensing platform based on a graphene-graphitic carbon nitride (g-C3N4) nanocomposite for ultrasensitive NSE detection. The g-C3N4 nanosheets and graphene nanosheets were synthesized via liquid exfoliation and integrated through self-assembly to form the nanocomposite. This nanocomposite was used to modify screen-printed carbon electrodes followed by covalent immobilization of anti-NSE antibodies. The unique properties of the graphene-g-C3N4 composite facilitated efficient antibody loading while also enhancing electron transfer efficiency and electrochemical response. Systematic optimization of experimental parameters was performed. The immunosensor exhibited a wide linear detection range of 10 pg/mL to 100 ng/mL and low limit of detection of 3 pg/mL for NSE along with excellent selectivity against interferences. Real serum matrix analysis validated the applicability of the developed platform for sensitive and accurate NSE quantifica-tion at clinically relevant levels. This novel graphene-g-C3N4 nanocomposite based electro-chemical immunoassay demonstrates great promise for early diagnosis of SCLC.

Abstract The vacuum-ultraviolet (VUV, 10–200 nm) imaging photodetector (PD) based on the wide bandgap semiconductor (WBGS) can realize a more detailed observation of solar storms than the silicon ones. Here, an 8 × 8 VUV PD array based on the semiconductor AlN with an ultra-wide bandgap is presented, exhibiting the shortest cutoff wavelength (203 nm) reported so far. The PD array with a Pt/AlN/SiC/Ti/Au photovoltaic structure shows an excellent selective response to VUV light, an extremely low dark current density of 2.85 × 10–11 A·cm−2@ -2 V, a responsivity of 0.054 A·W−1@ 0 V and an ultra-short rise time of 13 ns. Also, the clear boundaries and an obvious contrast between light and dark of the VUV image displayed in the imaging measurement indicate the good imaging ability of this PD array, which can be used for the imaging application with high signal-to-noise ratio and high response speed. These results provide rich experience for the development of VUV imaging PDs based on WBGSs both in their fabrication and the practical applications in VUV detection.

In response to the technical challenges of supporting tunnels in loose and fragmented surrounding rock with poor anchorage, strong dynamic pressure, and strong structural stress influences, extensive on-site surveys were conducted, and several typical problems of large deformation in coal mine tunnel surrounding rock and difficulty in rock control were summarized and analyzed. Based on the analysis of existing support technologies and theoretical foundations, a concept and method for the rapid support technology of reconstructing high-strength load-bearing structures were proposed. Taking the 11205 down-hill transport tunnel at Longbao Coal Mine in Guizhou as an engineering background, the causes of deformation and failure were analyzed. A combined support method of displacement and unloading for fragmented surrounding rock was designed in practice. The design plan and optimal parameter calculations for the roadside backfill wall were carried out, and a mechanical model for the load-bearing capacity of the roadside backfill wall was theoretically established. Its load-bearing strength was analyzed to determine the strength of the wall and its suitability and effectiveness with the surrounding rock of the tunnel. By integrating the FLAC3D numerical simulation software and the Python scripting language, the moth-flame optimization algorithm was applied to determine the optimal displacement parameters for the fragmented rock tunnel (wall thickness and unloading zone width). A new material for high-strength, high-toughness backfill support was developed. By displacing and reconstructing the weak wall body, the tunnel roof, backfill, and floor were reconstituted into an integral load-bearing structure. Industrial-scale trial results underground showed that after reconstructing the weak rock body of the tunnel, the new structure consisting of the roof, backfill, and floor fully utilized the surrounding rock’s own load-bearing capacity and resistance to deformation. The rock deformation stabilized, the convergence rate was generally less than 0.2 mm/d, with no significant deformation, and the results of the numerical simulation calculations were consistent with the engineering practice monitoring, indicating that the roadside backfill displacement support scheme has a good effect on controlling tunnels in loose and fragmented surrounding rock. This can provide a theoretical basis for the support and strength parameters of roadside backfill. Finally, the paper looked forward to deeper research into the technology of rapid support for reconstructed load-bearing structures.

Abstract This study aims to investigate the effectiveness of Intense Pulsed Light (IPL) therapy for chalazion treatment while also exploring potential variations in sensitivity among different types of chalazion. A total of 149 patients were selected to receive tobramycin combined with IPL treatment and tobramycin combined with hot compress. The treatment groups were divided into cystic type and granulomatous type according to different clinical manifestations. The course of treatment was 3 weeks. The improvement was based on the ultrasound measurement of the masses reduction of more than 50% or disappearance. In the IPL group, 17 (22.67%) cases were cured, 39 (52.00%) were effective, and 19 (25.33%) were ineffective. This includes: cystic type was cured in 3 (15.79%), effective in 5 (26.32%) cases, ineffective in 11 (57.89%) cases; granulomatous type was cured in 14 (25.00%) cases, effective in 34 (60.71%) cases, ineffective in 8 (14.29%) cases. In the hot compress group, 5 (6.76%) cases were cured, 16 (21.62%) cases were effective and 53 (71.62%) cases were ineffective. The cystic type was cured in 2 (8.00%) cases, effective in 3 (12.00%) cases and ineffective in 20 (80.00%) cases; the granulomatous type was cured in 3 (6.12%) cases, effective in 13 (26.53%) cases and ineffective in 33 (67.35%) cases. The cure rate and efficacy rate of IPL treatment is higher than that of hot compress treatment, the treatment effect of IPL treatment on granulomatous chalazion is better than that on cystic type.

Abstract Background The recruitment of thermogenic adipocytes in human fat depots markedly improves metabolic disorders such as type 2 diabetes mellitus (T2DM). However, identification and quantification of thermogenic cells in human fats, especially in metabolic disorders patients, remains a major challenge. Here, we aim to provide a stringent validation of human thermogenic adipocyte signature genes, and construct transcriptome-based models to quantify the browning degree of human fats. Methods Evidence from RNA-seq, microarray analyses and experimental approaches were integrated to isolate robust human brown-like fat signature genes. Meta-analysis was employed to validate the performance of known human brown-like fat marker genes. Autoencoder was used to reveal the browning levels of human adipose samples for supervised machine learning. Ensemble machine learning was applied to devised molecular metrics for quantifying browning degree of human fats. Obesity and T2DM datasets were used to validate the performance of the molecular metrics in adipose-related metabolic disorders. Results Human brown-like adipocytes were heterogeneous populations which showed distinct transcriptional patterns and biological features. Only DHRS11, REEP6 and STX11 were robust signature genes that were consistently up-regulated in different human brown-like fats, especially in creatine-induced UCP1-independent adipocytes. The molecular metrices based on the expression patterns of the three signature genes, named human browning capacity index (HBI) and absolute HBI (absHBI), were superior to 26 traditional human brown-like fat marker genes and previously reported browning classifier in prediction of browning levels of human adipocytes and adipose tissues as well as primary cell cultures upon various physiological and pharmacological stimuli. Notably, these molecular metrics also reflected the insulin sensitivity and glucose-lipid metabolic activity of human adipose samples from obesity and T2DM patients. Conclusions In summary, this study provides promising signatures and computational tools for evaluating browning levels of human adipose samples in response to physiological and medical intervention. The metrices construction pipeline provides an alternative approach for training machine learning models using unlabeled samples.

Global navigation satellite system-reflection (GNSS-R) sea surface altimetry based on satellite constellation platforms has become a new research direction and inevitable trend, which can meet the altimetric precision at the global scale required for underwater navigation. At present, there are still research gaps for GNSS-R altimetry under this mode, and its altimetric capability cannot be specifically assessed. Therefore, GNSS-R satellite constellations that meet the global altimetry needs to be designed. Meanwhile, the matching precision prediction model needs to be established to quantitatively predict the GNSS-R constellation altimetric capability. Firstly, the GNSS-R constellations altimetric precision under different configuration parameters is calculated, and the mechanism of the influence of orbital altitude, orbital inclination, number of satellites and simulation period on the precision is analyzed, and a new multilayer feedforward neural network weighted joint prediction model is established. Secondly, the fit of the prediction model is verified and the performance capability of the model is tested by calculating the R2 value of the model as 0.9972 and the root mean square error (RMSE) as 0.0022, which indicates that the prediction capability of the model is excellent. Finally, using the novel multilayer feedforward neural network weighted joint prediction model, and considering the research results and realistic costs, it is proposed that when the constellation is set to an orbital altitude of 500 km, orbital inclination of 75° and the number of satellites is 6, the altimetry precision can reach 0.0732 m within one year simulation period, which can meet the requirements of underwater navigation precision, and thus can provide a reference basis for subsequent research on spaceborne GNSS-R sea surface altimetry.

This study focuses on the improvement of path planning efficiency for underwater gravity-aided navigation. Firstly, a Depth Sorting Fast Search (DSFS) algorithm was proposed to improve the planning speed of the Quick Rapidly-exploring Random Trees∗ (Q-RRT∗) algorithm. A cost inequality relationship between an ancestor and its descendants was derived, and the ancestors were filtered accordingly. Secondly, the underwater gravity-aided navigation path planning system was designed based on the DSFS algorithm, taking into account the fitness, safety, and asymptotic optimality of the routes, according to the gravity suitability distribution of the navigation space. Finally, experimental comparisons of the computing performance of the ChooseParent procedure, the Rewire procedure, and the combination of the two procedures for Q-RRT∗ and DSFS were conducted under the same planning environment and parameter conditions, respectively. The results showed that the computational efficiency of the DSFS algorithm was improved by about 1.2 times compared with the Q-RRT∗ algorithm while ensuring correct computational results.

This paper addresses the escalating demand for aquaculture products by proposing an edge-cloud solution for precision aquaculture. Despite technological advancements, challenges persist in the aquaculture industry, including labor shortages and inaccurate data analysis. The project focuses on water quality monitoring, employing IoT sensors in an edge computing environment to collect real-time parameters and using a camera module to analyze the growth of prawns. Local processing minimizes bandwidth requirements and latency, with data transmitted to the cloud for analysis and graphical visualization. In this paper, we present a unique edge-cloud architecture for precision aquaculture tailored to small-scale and resource-constrained farmers. The paper introduces a federated learning framework, utilizing a distributed computing architecture, where the edge environment acts as the client node, training a local machine learning model. The cloud server aggregates model weights from diverse clients, creating a robust global model without compromising individual data privacy. This comprehensive solution aims to improve aquaculture efficiency, address production challenges, reduce high consumption of network bandwidth, and ensure sustainable practices.

Abstract Objectives The timing of tracheostomy for critically ill patients on mechanical ventilation (MV) is a topic of controversy. Our objective was to determine the most suitable timing for tracheostomy in patients undergoing MV. Design Retrospective cohort study. Setting and participants One thousand eight hundred eighty-four hospitalisations received tracheostomy from January 2011 to December 2020 in a Chinese tertiary hospital. Methods Tracheostomy timing was divided into three groups: early tracheostomy (ET), intermediate tracheostomy (IMT), and late tracheostomy (LT), based on the duration from tracheal intubation to tracheostomy. We established two criteria to classify the timing of tracheostomy for data analysis: Criteria I (ET ≤ 5 days, 5 days 10 days) and Criteria II (ET ≤ 7 days, 7 days 14 days). Parameters such as length of ICU stay, length of hospital stay, and duration of MV were used to evaluate outcomes. Additionally, the outcomes were categorized as good prognosis, poor prognosis, and death based on the manner of hospital discharge. Student’s t-test, analysis of variance (ANOVA), Mann–Whitney U test, Kruskal–Wallis test, Chi-square test, and Fisher’s exact test were employed as appropriate to assess differences in demographic data and individual characteristics among the ET, IMT, and LT groups. Univariate Cox regression model and multivariable Cox proportional hazards regression model were utilized to determine whether delaying tracheostomy would increase the risk of death. Results In both of two criterion, patients with delayed tracheostomies had longer hospital stays (p