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Abstract Background Blastocyst morphology has been demonstrated to be associated with ploidy status. Existing artificial intelligence models use manual grading or 2D images as the input for euploidy prediction, which suffer from subjectivity from observers and information loss due to incomplete features from 2D images. Here we aim to predict euploidy in human blastocysts using quantitative morphological parameters obtained by 3D morphology measurement. Methods Multi-view images of 226 blastocysts on Day 6 were captured by manually rotating blastocysts during the preparation stage of trophectoderm biopsy. Quantitative morphological parameters were obtained by 3D morphology measurement. Six machine learning models were trained using 3D morphological parameters as the input and PGT-A results as the ground truth outcome. Model performance, including sensitivity, specificity, precision, accuracy and AUC, was evaluated on an additional test dataset. Model interpretation was conducted on the best-performing model. Results All the 3D morphological parameters were significantly different between euploid and non-euploid blastocysts. Multivariate analysis revealed that three of the five parameters including trophectoderm cell number, trophectoderm cell size variance and inner cell mass area maintained statistical significance (P

Abstract The nematode Caenorhabditis elegans is widely employed as a model organism to study basic biological mechanisms. However, transgenic C. elegans are generated by manual injection, which remains low-throughput and labor-intensive, limiting the scope of approaches benefitting from large-scale transgenesis. Here, we report a robotic microinjection system, integrating a microfluidic device capable of reliable worm immobilization, transfer, and rotation, for high-speed injection of C. elegans. The robotic system provides an injection speed 2-3 times faster than that of experts with 7–22 years of experience while maintaining comparable injection quality and only limited trials needed by users to become proficient. We further employ our system in a large-scale reverse genetic screen using multiplexed alternative splicing reporters, and find that the TDP-1 RNA-binding protein regulates alternative splicing of zoo-1 mRNA, which encodes variants of the zonula occludens tight junction proteins. With its high speed, high accuracy, and high efficiency in worm injection, this robotic system shows great potential for high-throughput transgenic studies of C. elegans.

Abstract Climate change is shifting the experience of energy hardship. Here we examine the effect of the intensity, frequency, and duration of temperature extremes on energy hardship, and how this risk is shaped by individual, housing and neighbourhood resiliencies across Australia, using nationally representative data (269,500 observations) on energy hardship linked to temperature records between 2005 and 2021. Findings suggest that the risk of energy hardship increases with more intense extreme heat and cold, with greater risks for older individuals, lone-person or single-parent households, and rental tenants. These vulnerabilities can be offset by quality housing and renewable energy installations. Energy hardship risks under moderate and high emissions global warming scenarios are projected to increase by 0.1%−2.6% and 0.6%−3.3% respectively in the long run. Energy hardship will remain a concern despite raising temperatures, especially for colder regions less prepared for heat and populations with individual vulnerabilities and lacking housing and neighbourhood adaptations.

Abstract Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream cancer treatment strategy, with ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor glutathione peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

Abstract Aims It is unclear whether activated partial thromboplastin time (aPTT) or anti‐Xa is more accurate for monitoring heparin anticoagulation in mechanical circulatory support (MCS) patients. This study investigates the relationship between aPTT and anti‐Xa in MCS patients and identifies predictors of discordance. Methods and results aPTT and anti‐Xa were simultaneously measured in a prospective cohort of MCS patients receiving unfractionated heparin at a tertiary academic medical centre. Therapeutic aPTT and anti‐Xa levels were 60–100 s and 0.3–0.7 IU/mL, respectively, and concordance was defined as both levels being subtherapeutic, therapeutic, or supratherapeutic. To identify predictors of discordance, both a machine learning random forest model and a multivariate regression model were applied to patient demographics, device type, and 14 laboratory variables; 23 001 pairs of simultaneously measured aPTT/anti‐Xa were collected from 699 MCS patients. aPTT and anti‐Xa were concordant in 35.5% of paired observations and discordant in 64.5% (aPTT > antiXa 61.5%; aPTT antiXa) was associated with high INR, eGFR, and total bilirubin, as well as low platelets, haemoglobin, pre‐albumin, white blood cell count, and haptoglobin. Total artificial heart and durable ventricular assist devices were more likely to be associated with aPTT > anti‐Xa than temporary MCS devices. Conclusions aPTT and anti‐Xa were frequently discordant in MCS patients receiving heparin anticoagulation. Clinical conditions common in MCS patients such as concurrent warfarin use, malnutrition, haemolysis, and thrombocytopenia, as well as durable type of MCS devices were associated with a high aPTT relative to anti‐Xa.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting cells that are important for initiating and regulating both innate and adaptive immune responses. As a crucial component of the immune system, DCs have a pivotal role in the pathogenesis and clinical treatment of CRC. DCs cross-present tumor-related antigens to activate T cells and trigger an antitumor immune response. However, the antitumor immune function of DCs is impaired and immune tolerance is promoted due to the presence of the tumor microenvironment. This review systematically elucidates the specific characteristics and functions of different DC subsets, as well as the role that DCs play in the immune response and tolerance within the CRC microenvironment. Moreover, how DCs contribute to the progression of CRC and potential therapies to enhance antitumor immunity on the basis of existing data are also discussed, which will provide new perspectives and approaches for immunotherapy in patients with CRC.

Abstract Background The fat-to-muscle mass ratio (FMR), integrating the antagonistic effects of fat and muscle mass, has been suggested as a valuable indicator to assess cardiometabolic health independent of overall adiposity. However, the specific associations of total and regional FMR with cardiometabolic risk are poorly understood. We aimed to examine sex-specific associations of total and regional FMR with single and clustered cardiometabolic risk factors (CRFs). Methods 13,505 participants aged 20 years and above were included in the cross-sectional study. Fat mass and muscle mass were assessed using a bioelectrical impedance analysis device. FMR was estimated as fat mass divided by muscle mass in corresponding body parts (whole body, arm, leg, and trunk). Clustered CRFs was defined as the presence of two or more risk factors, including hypertension, elevated blood glucose, dyslipidemia, insulin resistance (IR), and hyperuricemia. IR was assessed by the triglyceride glucose (TyG) index. Multivariable logistic regression models were applied to explore the associations of FMR in the whole body and body parts with single and clustered CRFs. Results The odds ratios (ORs) increased significantly for all single and clustered CRFs with the per quartile increase of total and regional FMR in both sexes (P for trend

Abstract The vertical tube indirect evaporative cooler (VTIEC) could be preferred one to air-conditioning buildings if its water film quality could be improved. This paper proposed a new VTIEC with inner grooved tubes to improve the water film quality and obtained its performance by experimental method. The results indicated that inner grooved tubes have positive effects on the water film and performance of the new VTIEC. A low working air enthalpy at inlet can significantly improve the total cooling capacity from evaporation, and then VTIEC performance. In this paper conditions, the velocity ratio of 1.52 of the produced air to the working air is better one condition compared to 1.01 and 2.28. The produced air velocity is positive effect on the cooling capacity per unit area until the produced air velocity of about 4.05 m/s and is negative effect on COP. The maximum unit cooling capacity, wet-bulb efficiency and COP are 307.74W/m2, 81.7% and 44.97.The results will promote the application of the new VTIEC.

Abstract Due to intermittent renewable energy and fluctuating load demand, distribution networks with renewable distributed generation (DG) installations are more likely to suffer voltage issues and significant power losses. The performance of conservation voltage regulation (CVR) schemes may be adversely affected by the undesirable voltage profile at specific nodes. This paper aims to reduce power losses in CVR‐implemented networks by optimally planning new renewable DGs without changing the existing ones. A scenario‐based optimal renewable DG planning model is proposed with a novel scenario formation method. The uncertainties of load demand and renewables are captured jointly and formed into a finite number of scenarios based on a multivariate Gaussian mixture model (MultiGMM). The locations and capacities of different types of new renewable DGs are optimally planned for CVR performance improvements on power loss saving by aggregating the operation status and probabilities of the scenarios using mixed‐integer non‐linear programming (MINLP). A time‐series simulation is formulated for accuracy verification. The results of case studies show that the proposed model can significantly reduce power losses, active load demand, and reactive load demand. The accuracy of the planning results can be guaranteed with fewer scenarios compared to a widely used classical scenario‐based planning method.

Objectives: Studies have increasingly focussed on the relationship between periodontitis (PD) and preeclampsia (PE). However, conclusions have not been consistent, and it is unclear whether any causal relationship exists between them and whether causality is bidirectional. This study employed Mendelian randomisation (MR) analysis to investigate the potential bidirectional causal relationship between PD and PE. Methods: Genetic variants strongly linked to PD (17,353 cases and 28,210 controls), chronic periodontitis (CP; 1817 cases and 2215 controls), aggressive periodontitis (AgP; 851 cases and 6580 controls), and PE (7212 cases and 194,266 controls) in the genome-wide association study (GWAS) of European ancestry were used as instrumental variables (IVs). Inverse variance weighting (IVW) served as the primary method for causal inference. MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) was utilised to analyse horizontal pleiotropy. Cochrane Q tests and leave-one-out analyses were used to assess heterogeneity and stability amongst IVs. Results: The MR analysis revealed no causal impacts of PD or its 2 subtypes—CP and AgP—on PE. Similarly, no significant causal effect of PE on PD was found in the reverse-MR analysis (IVW odds ratio, 0.97; 95% confidence interval, 0.91–1.05; P = .58). The findings from MR–Egger, weighted median, weighted mode, and the simple modelling approaches, as well as the pleiotropy and sensitivity analyses, aligned with those of the IVW method. Conclusions: The MR analysis suggests no bidirectional causal relationship between PD and PE; hence, PD and PE might not increase or prevent the risk of one other. Clinical Relevance: Genetically, periodontitis or its subtypes chronic periodontitis and aggressive periodontitis may not require specific clinical attention to prevent the development of preeclampsia.

Optimizing blasting parameters is of paramount importance in minimizing overbreak during tunneling. Hence, this paper proposed an intelligent approach, which integrates separate parameter optimization based on varying rock mass qualities, with the objective of reducing overbreak. This novel intelligent method constructs a comprehensive model with three distinct functions, which can provide precise overbreak prediction, analyze the mechanisms by which input parameters influence overbreak, and integrate feature importance into the blasting parameters optimization process. First, the hyperparameters of seven tree-based algorithms were optimized using the Sparrow Search Algorithm (SSA), and the best predictive model was selected by comparing various performance metrics. Then, the importance and influencing mechanisms of input features on overbreak were revealed through the utilization of the Shapley Additive Explanation. Subsequently, interactions among crucial parameters were investigated, and their design values were recommended. Finally, a novel parameter optimization method was employed to reduce overbreak, which combines the conclusions drawn from the importance analysis of input features with SSA through three key steps: modification of the initial position, expanding the search scope, and neighborhood perturbation. Compared to the unimproved methods, the proposed approach can significantly reduce post-blast overbreak areas in different sections of the tunnel by 12.8 % and 16.4 %, respectively.

Despite the pressing demand for integrated spectrometers, a solution that deliver high-performance while being practically operated is still missing. Furthermore, current integrated spectrometers lack reconfigurability in their performance, which is highly desirable for dynamic working scenarios. This study presents a viable solution by demonstrating a user-friendly, reconfigurable spectrometer on silicon. At the core of this innovative spectrometer is a programmable photonic circuit capable of exhibiting diverse spectral responses, which can be significantly adjusted using on-chip phase shifters. The distinguishing feature of our spectrometer lies in its inverse design approach, facilitating effortless control and efficient manipulation of the programmable circuit. By eliminating the need for intricate configuration, our design reduces power consumption and mitigates control complexity. Additionally, our reconfigurable spectrometer offers two distinct operating conditions. In the Ultra-High-Performance mode, it is activated by multiple phase-shifters and achieves exceptional spectral resolution in the picometer scale while maintaining broad bandwidth. On the other hand, the Ease-of-Use mode further simplifies the control logic and reduces power consumption by actuating a single-phase shifter. Although this mode provides a slightly degraded spectral resolution of approximately 0.3 nm, it prioritizes ease of use and is well-suited for applications where ultra-fine spectral reconstruction is not a primary requirement.

Abstract Purpose Investigate the clinical characteristics of splenomegaly secondary to acute pancreatitis (SSAP) and construct a nomogram prediction model based on Lasso-Logistic regression. Methods A retrospective case-control study was conducted to analyze the laboratory parameters and computed tomography (CT) imaging of acute pancreatitis (AP) patients recruited at Xuanwu Hospital from December 2014 to December 2021. Lasso regression was used to identify risk factors, and a novel nomogram was developed. The performance of the nomogram in discrimination, calibration, and clinical usefulness was evaluated through internal validation. Results The prevalence of SSAP was 9.2% (88/950), with the first detection occurring 65(30, 125) days after AP onset. Compared with the control group, the SSAP group exhibited a higher frequency of persistent respiratory failure, persistent renal failure, infected pancreatic necrosis, and severe AP, along with an increased need for surgery and longer hospital stay (P

Abstract Background Colon cancer remains a major health concern worldwide, with genetic factors playing a crucial role in its development. Toll-like receptors (TLRs) has been implicated in various cancers, but their role in colon cancer is not well understood. This study aims to identify functional polymorphisms in the promoter and 3′UTR regions of TLRs and evaluate their association with colon cancer susceptibility. Methods We conducted a case-control study involving 410 colon cancer patients and 410 healthy controls from the Chinese population. Genotyping of polymorphisms in TLR3, TLR4, TLR5 and TLR7 was performed using PCR-RFLP and TaqMan MGB probes. Using logistic regression analysis, we evaluated the association of TLRs polymorphisms and the susceptibility to colon cancer. To understand the biological implications of the TLR4 rs1927914 polymorphism, we conducted functional assays, including luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Results Our results demonstrated that the G-allele of the TLR4 rs1927914 polymorphism is significantly associated with a decreased risk of colon cancer (OR = 0.68, 95%CI = 0.50–0.91). Stratified analysis showed that TLR4 rs1927914 AG or GG genotype contributed to a decreased risk of colon cancer among younger individuals (OR = 0.52, 95%CI = 0.34–0.81), males (OR = 0.58, 95%CI = 0.38–0.87), non-smokers (OR = 0.58, 95%CI = 0.41–0.83) and non-drinker with OR (95%CI) of 0.66 (0.46–0.93). Functional assays demonstrated that in HCT116 and LOVO colon cancer cells, the luciferase activity driven by the TLR4 promoter with the rs1927914A allele was 5.43 and 2.07 times higher, respectively, compared to that driven by the promoter containing the rs1927914G allele. Electrophoretic mobility shift assay (EMSA) results indicated that the rs1927914G allele enhanced transcription factor binding. Using the transcription factor prediction tool, we found that the G allele facilitates binding of the repressive transcription factor Oct1, while the A allele does not. Conclusion The TLR4 rs1927914 polymorphism influence the susceptibility to colon cancer, with the G allele offering a protective effect through modulation of gene expression. These insights enhance our understanding of the genetic determinants of colon cancer risk and highlight TLR4 as a promising target for cancer prevention strategies.

Abstract Background Lung cancer, with its high morbidity and mortality, presents a major significant public health challenge. CD147, linked to cancer progression and metastasis, is a promising therapeutic target, including for lung cancer. The genetic variation may influence the expression of the gene and consequently the risk of lung cancer. This study aims to investigate single nucleotide polymorphisms (SNPs) in CD147 to understand their association with the risk of developing lung cancer in the Han Chinese population. Methods A hospital-based case–control investigation was conducted, enrolling 700 lung cancer patients and 700 cancer-free controls. TagSNPs were selected using Haploview v4.2, and genotype data from the 1000 Genomes Project database were utilized. The selected SNPs (rs28992491, rs67945626, and rs79361899) within the CD147 gene were evaluated using the improved multiple ligation detection reaction method. Statistical analysis included chi-square tests, logistic regression models, and interaction analyses. Results Baseline characteristics of the study population showed no significant differences in gender distribution between cases and controls, but there was a notable difference in smoking rates. No significant associations were found between the three TagSNPs and lung cancer susceptibility in the codominant model. However, stratification analyses revealed interesting findings. Among females, the rs79361899 AA/AG genotype was associated with an increased risk of lung cancer. In individuals aged ≥ 65 years old, the rs28992491 GG and rs79361899 AA genotypes were linked to a higher susceptibility. Furthermore, an interaction analysis demonstrated significant genotype × gender interactions in the rs79361899 recessive model, indicating an increased lung cancer risk in female carriers of the heterozygous or homozygous polymorphic genotype. Conclusions CD147 polymorphisms play an important role in lung cancer development, particularly in specific subgroup of age and gender. These findings highlight the significance of incorporating genetic variations and their interactions with demographic factors in comprehending the intricate etiology of lung cancer.

To improve the microstructure and properties of Cu-Sn-Ti brazing alloy through component control, the effect of Si on the microstructure and properties of Cu-20Sn-15Ti brazing filler metals was studied using scanning electron microscopy, X-ray diffraction, and EDS energy spectrum analysis. The results show that the microstructure of Cu-20Sn-15Ti brazing filler metal is composed of large-sized polygonal CuSn3Ti5 phase, eutectic structure and α-Cu phase. A small amount of Si (≤ 2.0wt%) refines the polygonal-shaped CuSn3Ti5 phase in the brazing filler metal and generates small-sized Si3Ti5 phase. In contrast, a larger amount of Si (≥ 3.0wt%) differentiates the polygonal-shape CuSn3Ti5 phase, reduces the proportion of eutectic structure, and increases the content and size of the Si3Ti5 phase. When the Si content increases to 5.0wt%, the filler metal no longer generates polygonal-shaped CuSn3Ti5 phase and eutectic structure. Instead, Ti primarily forms Ti5Si3 phase, and the microstructure mainly consists of Ti5Si3 phase, α- Cu phase, Cu41Sn11 phase, and a small amount of strip-shaped CuSn3Ti5 phase. Compared with Cu and Sn, Si has a stronger chemical affinity with Ti and preferentially reacts with Ti to form Ti5Si3 phase. The three-dimensional structure of Ti5Si3 phase is prismatic and exhibits agglomerated growth characteristics. The coarse strip Ti5Si3 phase has central or lateral pore defects, which are mainly related to the growth mechanism. As the Si content increases, the shear strength of the filler metals shows a trend of “increasing-decreasing-increasing”, and the fracture morphology transitions from a mixed morphology of quasi-cleavage fracture and cleavage fracture to cleavage fracture. The CuSn3Ti5 phase is prone to breakage and cracking, becoming the source of cracking. The presence of coarse CuSn3Ti5 phase in different states can deteriorate the shear strength of the brazing filler metals to some extent.

Background: Periodontitis is a chronic progressive disease and the leading cause of tooth loss in adults. Recent studies have shown the impact of oral microbial communities on systemic health and diseases such as cancer, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, diabetes, hypertension, and Alzheimer's disease. In previous case control studies investigatin the relationship between periodontal disease and the oral microbiota, little attention has been paid to the intersections of these domains. Methods: Here, we used high-throughput 16S rRNA sequencing to analyse the differences in the microbial composition in saliva between a group of patients with chronic periodontitis (C; n = 51) and a healthy control group (H; n = 61) and predicted the functional gene composition by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. Results: We found significant alterations in oral microbial diversity between C and H (P = 0.002). Sixteen genera were significantly different between C and H, and 15 of them were enriched in C linear discriminant analysis (LDA > 2). Fifty functional genes were significantly different between C and H, and 34 of them were enriched in C (P < .025). Conclusions: Periodontitis is associated with significant changes in the oral microbial community.

Introduction: Diuretics are the mainstay of maintaining and restoring euvolemia in the management of heart failure. Loop diuretics are often preferred, however, combination diuretic therapy (CDT) with a thiazide diuretic is often used to overcome diuretic resistance and increase diuretic effect. We performed an analysis of the GUIDE-IT study to assess all-cause mortality and time to first hospitalizations in patients necessitating CDT. Methods: Patients from the GUIDE-IT dataset were stratified by their requirement for CDT with a thiazide to achieve euvolemia. A total of 894 patients were analyzed, 733 of which were treated with loop diuretics alone vs 161 used either chlorothiazide or metolazone in addition to loop diuretics. Kaplan-Meir curves were derived with log-rank p-values to evaluate for differences between the groups. Results: There was no significant difference in all-cause mortality regardless of CDT utilization status (mean survival of 612.704 days vs 603.326 days, p = 0.083). On subgroup analysis, there was no significant difference in all-cause mortality amongst those using loop diuretics compared to CDT in the BNP-guided therapy group, (mean survival time 576.385 days vs 620.585 days, p = 0.0523), nor the control group (614.1 days vs 588.9 days; p = 0.5728). Time to first hospitalization was reduced in all using CDT compared to loop diuretics alone (280.5 days vs 407.2 days, p

So as to extend the application of upper bound limit analysis for slope stability in open-pit mine, this paper analyzed failure mechanism of rock mass when shear failure occurred based on plastic mechanics principles, and combined with discrete mathematical theory and least square principle to propose a visualization method of logarithmic spiral. At the same time, the visualization method was applied to engineering practice for slope stability in open-pit mine, and cycle algorithm of stability analysis for open-pit mine slope was proposed through energy balance conditions, then stability analysis results were evaluated reasonably through uniting with limit equilibrium method. The results show that visualization method of logarithmic spiral proposed in this paper is highly consistent with original curve, and can ensure correlation coefficient square is greater than 0.9995. What is more, upper bound limit analysis method has a superhigh accuracy in slope engineering. At the same time, the most dangerous sliding surface obtained by this method can satisfy the requirements of velocity separation, which solved velocity problems during the process of slope evolution. Therefore, the method proposed in this paper has a stronger application in the field of open-pit mining.

The heat transfer characteristics of smooth and honeycomb staggered labyrinth seals were investigated using the conjugate heat transfer method. Three pressure ratios (π = 1.2, 1.6, and 2.0), three rotational speeds (RPM = 0, 10,000, and 20,000), and two wall-to-fluid temperature ratios (TR = 0.4 and −0.67) are considered to explore the influence of centrifugal force and centrifugal buoyancy. The results indicate that the heat transfer coefficient of staggered labyrinth seals increases with pressure ratio due to the increased flow velocity and the thinner boundary layer. As a result of the interaction of inertia force and centrifugal force, some enhancement positions of heat transfer coefficient shift slightly. Notably, centrifugal buoyancy has a negative impact on heat transfer at TR = −0.67, but a positive impact at TR = 0.4. When TR = −0.67, there is a peak of the heat transfer coefficient with increased rotational speed due to centrifugal buoyancy. In addition, the heat transfer coefficient at TR = −0.67 is lower than that at TR = 0.4, especially at high rotational speeds. It is proposed that heat transfer correlations be developed by incorporating the Taylor number and rotating Grachev number.

Pluripotent stem cells were generated through the electroporation of episomal plasmids, containing crucial reprogramming factors, into skin fibroblasts extracted from a female Alzheimer’s patient harboring the PSEN1 709 T > C (p.Phe237Leu) heterozygous mutation. The pluripotent stem cells exhibit a normal karyotype and express pivotal stem cell markers including TRA-1-60, Nanog, SOX2, and OCT4. Furthermore, their capacity to differentiate into the three germ layers in in vivo teratoma experiments has been substantiated. The pluripotent stem cell line can serve as a cellular model for Alzheimer’s disease, offering significant value in elucidating the pathogenesis and therapeutic strategies of the disease.

ABSTRACT: Toxoplasma gondii (T. gondii) is an intracellular protozoan that can cause toxoplasmosis in all warm-blooded hosts. This study focused on the prevalence and genetic characterize of T. gondii in ducks from Fujian province, China. Genomic DNA was extracted from duck tissue samples (heart, liver, lung, and muscle). To assess the genetic diversity of the T. gondii isolates, it was determined by using multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. A total of 586 ducks from 5 cities in Fujian province were tested, and 35 (6.0%) of which were found to be positive for the T. gondii B1 gene. Further genotyping of these positive samples at 10 genetic markers (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico) using PCR-RFLP revealed that one tissue samples (heart samples from Fuzhou ducks) were identified as Type I (ToxoDB#10). This study is the first report on the prevalence and genetic characterization of T. gondii in ducks in Fujian province, and Type I (ToxoDB#10) is found in ducks in China for the first time. The findings document the genetic characterization of T. gondii in free-range ducks from Fujian Province, thereby enriching the understanding of T. gondii genetic diversity in China. Moreover, these results provide essential data support for further prospective studies and underscores the “One Health” concept, emphasizing the integral link among human, animal, and environmental health.

Abstract Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype. Molecular stratification and target therapy bring clinical benefit for TNBC patients, but it is difficult to implement comprehensive molecular testing in clinical practice. Here, using our multi-omics TNBC cohort (N = 425), a deep learning-based framework was devised and validated for comprehensive predictions of molecular features, subtypes and prognosis from pathological whole slide images. The framework first incorporated a neural network to decompose the tissue on WSIs, followed by a second one which was trained based on certain tissue types for predicting different targets. Multi-omics molecular features were analyzed including somatic mutations, copy number alterations, germline mutations, biological pathway activities, metabolomics features and immunotherapy biomarkers. It was shown that the molecular features with therapeutic implications can be predicted including the somatic PIK3CA mutation, germline BRCA2 mutation and PD-L1 protein expression (area under the curve [AUC]: 0.78, 0.79 and 0.74 respectively). The molecular subtypes of TNBC can be identified (AUC: 0.84, 0.85, 0.93 and 0.73 for the basal-like immune-suppressed, immunomodulatory, luminal androgen receptor, and mesenchymal-like subtypes respectively) and their distinctive morphological patterns were revealed, which provided novel insights into the heterogeneity of TNBC. A neural network integrating image features and clinical covariates stratified patients into groups with different survival outcomes (log-rank P < 0.001). Our prediction framework and neural network models were externally validated on the TNBC cases from TCGA (N = 143) and appeared robust to the changes in patient population. For potential clinical translation, we built a novel online platform, where we modularized and deployed our framework along with the validated models. It can realize real-time one-stop prediction for new cases. In summary, using only pathological WSIs, our proposed framework can enable comprehensive stratifications of TNBC patients and provide valuable information for therapeutic decision-making. It had the potential to be clinically implemented and promote the personalized management of TNBC.

Abstract This paper proposes and investigates a novel 4H‐SiC trench MOSFET (TMOS) with integrated high‐K deep trench and gate dielectric (INHK‐TMOS). The integrated high‐K (INHK) consists of a high‐K gate dielectric and an extended high‐K deep trench dielectric in the drift region. Firstly, the high‐K gate dielectric together with the metal‐forming high‐K metal gate structure, which increases the gate oxide capacitance (COX), reduces the threshold voltage (VTH) and the specific on‐resistance (Ron,sp). Secondly, the extended high‐K deep trench dielectric not only modulates the electric field in the drift region by introducing a new electric field peak at the bottom of the high‐K deep trench dielectric, thereby enhancing the breakdown voltage (BV), but also improves the doping concentration (ND) of the drift region by the assist depletion effect of the high‐K dielectric, further optimizing the forward conduction characteristics. Simulation results demonstrate that when compared to the conventional TMOS, the INHK‐TMOS using HfO2 exhibits a 52.6% reduction in VTH, a 52.1% reduction in Ron,sp, a 20.3% increasement in BV and a 202.3% improvement in figure of merit.

Abstract Hippocampal place cells represent the position of a rodent within an environment. In addition, recent experiments show that the CA1 subfield of a passive observer also represents the position of a conspecific performing a spatial task. However, whether this representation is allocentric, egocentric or mixed is less clear. In this study we investigated the representation of others during free behavior and in a task where female mice learned to follow a conspecific for a reward. We found that most cells represent the position of others relative to self-position (social-vector cells) rather than to the environment, with a prevalence of purely egocentric coding modulated by context and mouse identity. Learning of a pursuit task improved the tuning of social-vector cells, but their number remained invariant. Collectively, our results suggest that the hippocampus flexibly codes the position of others in multiple coordinate systems, albeit favoring the self as a reference point.

On Earth, high-speed rotating blades and rotors experience hypergravity, which is mainly derived from centrifugal force. Aluminum alloys are widely used in high-speed rotating machines. In particular, 7075 aluminum has excellent properties, providing it with great potential for application in high-temperature rotating parts. In this work, the cracking behavior and microstructural evolution characteristics of high-speed rotating blades under different stresses were studied. A specifically designed instrument and blades with multiple necks were assembled, and the stress was tuned by adding weight to the blade tip. Each rotating blade cracked on its root neck, indicating that the gradient hypergravitational force decreased from the root to the tip. The degree of high-temperature cracking obviously increased with a sawtooth-like tip, but the degree of low-temperature cracking did not obviously increase with a smooth tip. A comparison under a constant uniaxial force required a greatly increased ultimate cracking strength that was approximately 10–18 times greater than that under hypergravitational force at the same temperature. Force analysis indicated that the coupling of hypergravitational forces in the normal direction and torsional forces in the tangential direction accelerated cracking. A uniaxial force caused grains to extend along the blade direction. However, a tangential force cut these extended grains to accelerate cracking and grain refining. In this study, real-world simulated service conditions for commercial alloys rotating at high speeds and a new understanding of the mechanical properties of alloys under various severe conditions were provided.

Abstract Deep vein thrombosis (DVT) is a common complication in patients with lower extremity fractures. Once it occurs, it will seriously affect the quality of life and postoperative recovery of patients. Therefore, early prediction and prevention of DVT can effectively improve the prognosis of patients. This study constructed different machine learning models to explore their effectiveness in predicting DVT. Five prediction models were applied to the study, including Extreme Gradient Boosting (XGBoost) model, Logistic Regression (LR) model, RandomForest (RF) model, Multilayer Perceptron (MLP) model, and Support Vector Machine (SVM) model. Afterwards, the performance of the obtained prediction models was evaluated by area under the curve (AUC), accuracy, sensitivity, specificity, F1 score, and Kappa. The prediction performances of the models based on machine learning are as follows: XGBoost model (AUC = 0.979, accuracy = 0.931), LR model (AUC = 0.821, accuracy = 0.758), RF model (AUC = 0.970, accuracy = 0.921), MLP model (AUC = 0.830, accuracy = 0.756), SVM model (AUC = 0.713, accuracy = 0.661). On our data set, the XGBoost model has the best performance. However, the model still needs external verification research before clinical application.

Abstract Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer (LARC) patients with microsatellite stable (MSS) / mismatch repair-proficient (pMMR) tumors is an attractive, but debatable strategy. This phase 2, multicenter, prospective, single-arm study enrolled patients from 6 centers from June 2021 to November 2022. Locally advanced rectal cancer (LARC, cT3-4aN0M0 and cT1-4aN1-2M0) patients aged ≥18 years with the distance from distal border of tumor to anal verge ≤10 cm (identified by Magnetic Resonance Imaging) were qualified for inclusion. The patients received long-course radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week) and three 21-day cycles capecitabine (850–1000 mg/m2, bid, po, day1–14) and three 21-day cycles tislelizumab (200 mg, iv.gtt, day8) as neoadjuvant. Total mesorectal excision (TME) was 6–12 weeks after the end of radiotherapy to achieve radical resection. A total of 50 patients were enrolled in this study. The pathological complete response rate was 40.0% [20/50, 95% confidence interval (CI): 27.61–53.82%], while 15 (30.0%, 95% CI: 19.1–43.75%), 9 (18.0%, 95% CI: 9.77–30.8%), 2 (4.0%, 95% CI: 1.10–13.46%) patients respectively achieved grade 1, 2, and 3 tumor regression. Treatment-related adverse events (TRAEs) occurred in 28 (56.0%) LARC patients, including 26(52.0%) with grade I-II and 2 (4.0%) with grade III (1 with grade 3 immune-related colitis and 1 with grade 3 rash). PD-1 blockade plus long-course chemoradiotherapy (CRT) showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients. A larger randomized controlled study is desired to further validate the above findings.

Oxidation is one of the main failure modes of superalloys, and the initial oxidation of a superalloy provides clues for its failure analysis. NiCo-based superalloys exhibit superior mechanical properties, but their oxidation behaviour is still debatable, especially in terms of the ratio of Ni/Co. Here, we show the effect of the Ni/Co ratio on the initial oxidation behaviour at the nanoscale by in situ environmental transmission electron microscopy (ETEM), which provides the initial microstructural changes in the γ/γ′ structure-based alloy. The results indicate that Ni-rich alloys exhibit better structural stability at high temperatures than Ni-deficient alloys. A high content of Ni promotes the formation of a dense oxide layer, inhibits the oxidation rate, and improves the oxidation resistance. This result will help to elucidate the basic process of oxide formation in NiCo-based single-crystal superalloys and provide ideas for improving their oxidation resistance for alloy design.

ABSTRACT: High broodiness in Muscovy ducks impedes animal husbandry growth. The interaction between endocrine hormones and gut microbiota has been proven to play a crucial role in reproductive performance, and whether it can regulate the broody behavior of Muscovy ducks requires further research. Nine laying ducks (Laying group) and nine broody ducks (Broodiness group) were selected. Corresponding serum, ileum, and cecum chyme were collected for further research. The results showed that, compared to the laying group, the serum concentration of prolactin decreased, while the levels of Mullerian inhibiting substance, follicle-stimulating hormone, and follistatin increased in the broodiness group (P < 0.05). 16S rDNA sequencing showed that, the broodiness group exhibited lower abundance levels of Rothia, Streptococcus, and Lactobacillus, whereas the abundance of Turicibacter, Aliicoccus, and Facklamia was higher in the ileum compared to the laying group (P < 0.05). In the cecum, the broodiness group exhibits a significant reduction in the abundance of Butyricicoccus and unclassified_f_Rikenellaceae, while the abundance of Christensenellaceae_R-7_group, Ruminococcus_torques_group, Parabacteroides, norank_f_Oscillospiraceae, Cloacibacillus, Sellimonas, Shuttleworthia, norank_f_UCG-010, unclassified_f_Lachnospiraceae, Oscillospira, Synergistes, Family_XIII_AD3011_group and Eubacterium_nodatum_group is higher compared to the laying group. A Spearman correlation analysis reveals that both in the ileum and cecum, serum hormones exhibit significant correlations with the top 20 abundant intestinal microbial genera. Among these, serum follistatin has most entries of significant correlations with the detected microbial genera (P < 0.05). In conclusion, the broody behavior of Muscovy ducks can be modulated by the interaction between hormones and gut microbiota. Notably, the relationship between Follistatin and the composition of gut microbiota, specifically Firmicutes, is the most prominent.

Introduction This retrospective study aimed to evaluate the prognostic value of [18F]FDG parameters in patients with visceral and bone metastatic hormone-sensitive prostate cancer (mHSPC).Patients and methods This analysis included the mHSPC patients who underwent [18F]FDG PET/CT at the initial diagnosis. Baseline characteristics were analyzed, and the uptake of [18F]FDG was quantified using SUVmax. Kaplan–Meier and Cox proportional hazard regression analysis were employed to evaluate the correlation between SUVmax and patient survival.Results Among the 267 patients enrolled, 90 (33.7%) presented with visceral metastases and 177 (66.3%) had bone metastases. The median follow-up for the visceral metastasis group was 35.5 months (IQR 26–53.8 months). The median overall survival for patients with lung, liver, or both metastases were 30, 21 and 17 months, respectively. Patients exhibiting higher [18F]FDG uptake in metastatic lesions experienced shorter overall survival (OS) in comparison to those with lower [18F]FDG uptake, both in the visceral metastases group (17 vs. 31 months, p = 0.002) and the bone metastases group (27.5 vs. 34.5 months, p

ABSTRACT: Mule ducks accumulate a large amount of fat in their livers when fed high-energy feed, which is predominantly used for producing fatty livers. Nevertheless, there is limited research on the molecular mechanisms underlying the formation of fatty liver in mule ducks. Fatty acid translocase (CD36) is a sensor for fatty acids and lipid metabolism regulator, which may play a crucial role in the accumulation of fat in the liver of mule ducks. In this study, Overexpression and CD36 gene interference for 24 h was followed by induction of liver cells with 400 µmol/L palmitic acid (PA) for 24 h. The results demonstrated that CD36 overexpression increased hepatic triglyceride content, lipid droplet deposition, oxidative stress, and cell apoptosis. However, interference with CD36 had the opposite effect. CD36 overexpression suppressed the expression of AMPK and CPT-1A genes but enhanced the expression of ACC1 and LKB1 genes, with interference yielding contrasting results. Additionally, the expression of CD36 inhibited the AMPK pathway, reduced AMPK phosphorylation, downregulated AMPK protein expression, and upregulated SREBP1 protein expression. This promoted palmitic acid-induced hepatocyte fat accumulation. In summary, CD36 promotes palmitic acid-induced fat accumulation in primary mule duck liver cells through the AMPK signaling pathway.

Objectives To explore a precise control pathway based on patient clinical variations for haemostatic clip usage in laparoscopic cholecystectomy (LC) through on-site research data from a teaching hospital. Specifically, the study aimed to: (1) to calculate the optimal haemostatic clip consumption in LC based on diagnostic grouping and surgical combinations, and (2) to provide evidence for cost containment of high-value medical consumables used in LC.Design Retrospective observational study.Setting Hospital in southwest China.Participants The inclusion criteria were set as inpatients whose medical records included International Classification of Diseases codes 1–3 with code 51.2300 (corresponding to LC surgery) and who were discharged on medical advice. A dataset containing 1001 patients without any haematological diagnoses was collected.Primary and secondary outcome measures Two ordered multinomial logit models were established to identify factors affecting haemostatic clip use in LC. Two-step clustering was used to form subgroups. The premodel included preoperative variables (acute cholecystitis and scarring/fibrotic atrophy), while the full model added intraoperative variables (anatomical variation and severe adhesions). Both models met application prerequisites.Results Key factors influencing haemostatic clip usage were identified, including acute cholecystitis, scarring/fibrotic atrophy, anatomical variation and severe adhesions. Consumption references for haemostatic clips were established for LC patients with good prognoses on discharge. The ordered multinomial logit model revealed that acute cholecystitis decreased the odds of using four or more clips (p

Purpose Performance status (PS), an essential indicator of patients’ functional abilities, is often documented in clinical notes of patients with cancer. The use of natural language processing (NLP) in extracting PS from electronic medical records (EMRs) has shown promise in enhancing clinical decision-making, patient monitoring, and research studies. We designed and validated a multi-institute NLP pipeline to automatically extract performance status from free-text patient notes. Patients and Methods We collected data from 19,481 patients in Harris Health System (HHS) and 333,862 patients from veteran affair’s corporate data warehouse (VA-CDW) and randomly selected 400 patients from each data source to train and validate (50%) and test (50%) the proposed pipeline. We designed an NLP pipeline using an expert-derived rule-based approach in conjunction with extensive post-processing to solidify its proficiency. To demonstrate the pipeline’s application, we tested the compliance of PS documentation suggested by the American Society of Clinical Oncology (ASCO) Quality Metric and investigated the potential disparity in PS reporting for stage IV non-small cell lung cancer (NSCLC). We used a logistic regression test, considering patients in terms of race/ethnicity, conversing language, marital status, and gender. Results The test results on the HHS cohort showed 92% accuracy, and on VA data demonstrated 98.5% accuracy. For stage IV NSCLC patients, the proposed pipeline achieved an accuracy of 98.5%. Furthermore, our analysis revealed a documentation rate of over 85% for PS among NSCLC patients, surpassing the ASCO Quality Metrics. No disparities were observed in the documentation of PS. Conclusion Our proposed NLP pipeline shows promising results in extracting PS from free-text notes from various health institutions. It may be used in longitudinal cancer data registries.

Abstract To elucidate the brain‐wide information interactions that vary and contribute to individual differences in schizophrenia (SCZ), an information‐resolved method is employed to construct individual synergistic and redundant interaction matrices based on regional pairwise BOLD time‐series from 538 SCZ and 540 normal controls (NC). This analysis reveals a stable pattern of regionally‐specific synergy dysfunction in SCZ. Furthermore, a hierarchical Bayesian model is applied to deconstruct the patterns of whole‐brain synergy dysfunction into three latent factors that explain symptom heterogeneity in SCZ. Factor 1 exhibits a significant positive correlation with Positive and Negative Syndrome Scale (PANSS) positive scores, while factor 3 demonstrates significant negative correlations with PANSS negative and general scores. By integrating the neuroimaging data with normative gene expression information, this study identifies that each of these three factors corresponded to a subset of the SCZ risk gene set. Finally, by combining data from NeuroSynth and open molecular imaging sources, along with a spatially heterogeneous mean‐field model, this study delineates three SCZ synergy factors corresponding to distinct symptom profiles and implicating unique cognitive, neurodynamic, and neurobiological mechanisms.

Electro-synthetic fuel is proposed as an approach to achieve net-zero carbon emissions for heavy-duty internal combustion engines and meet carbon neutrality targets. This method is based on high temperature co-electrolysis using a solid oxide electrolysis cell (SOEC) coupled with Fisher-Tropsch (FT) synthesis due to its high efficiency and carbon recycling capacity. To access the techno-economic viability of this pathway and identify the key elements impacting the cost of electro-synthetic fuels, a comprehensive techno-economic model is constructed. This model aims to offer cost cutting guidance and includes SOEC, FT, and techno-economic sub-models, with SOEC and FT validated using literature data. The cost breakdown and sensitivity analysis indicate that heating costs, electricity prices, and stack lifetime are critical factors in reducing the cost of electro-synthetic fuel. Three alternative system layouts that fully utilize thermal and chemical energy are proposed to address the significant heating expense issue. Among these, the optimal system design lowers costs by approximately 5.3 %. Furthermore, this work introduces the contradiction between high performance, high stability, and low-cost accounting for the SOEC lifetime, which is bounded by operating current density. When considering the degradation and replacement of SOEC stacks, the long-term profitability of operating SOEC at a current density of 500 mA/cm2 is superior to that of 850 mA/cm2. Despite the most effective layout being currently unprofitable, it is anticipated that in the future, carbon trade, renewable electricity and technological advancements will drive the cost of electro-synthetic fuel to become competitive with that of diesel.

Abstract Centromere protein A (CENP‐A), a centromere‐specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure‐activity relationship (SAR) study of the cell‐cycle‐arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)‐6‐Br‐JP18 and (+)‐6‐Cl‐JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X‐ray crystallography analysis reveals that both molecules bind to the colchicine‐binding site of β‐tubulin. Treatment of human cells with microtubule‐targeting agents (MTAs), including these two compounds, results in CENP‐A accumulation by destabilizing Cdh1, a co‐activator of the anaphase‐promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP‐A accumulation using small‐molecule tools and highlights the role of Cdh1 in CENP‐A proteolysis.

ABSTRACT: The aim of this study was to examine the effects of NH3 variations across different positions within a cage-reared duck house on the egg production performance and fecal microbiome in Muscovy ducks. Totals of 3,168 female Muscovy ducks (180 ± 2 d) were randomly assigned to 1,056 cages. From d 293 to 300, the egg production rate and levels of NH3, H2S, CO2, temperature, humidity, light intensity, and dust particles were recorded. Two spatial distribution-based experimental classification methods were applied, one grouping ducks into Front, Middle, and End categories, and the other into First, Second, and Third layers. On d 300, serum and feces samples were collected for further analysis. The result showed that both the egg production rate and serum PROG level in the Front were higher than End (P < 0.05). However, no significant differences were found among the First, Second, and Third groups. Among the environmental factors, ammonia (NH3) is a major harmful gas in cage-reared duck houses, with observed concentrations showing a gradient from lower levels in the Front group to higher levels in the Middle group (P < 0.05), and even higher levels in the End group (P < 0.05). Gene sequencing of the 16S rRNA gene revealed a higher relative abundance of Firmicutes in both the Front and Middle groups compared to the End group (P < 0.05). Specifically, within the Firmicutes phylum, the relative abundance of Lactobacillus and Romboutsia was notably higher in the Front group compared to both the Middle and End groups (P < 0.05). What's more, the abundance of Lactobacillus had a negative correlation with NH3 concentration and positive correlation with egg production rate. In conclusion, NH3 concentrations showed variations across different areas of the cage-reared duck house, with higher levels detected at the rear. The elevated NH3 level was identified as the main factor negatively impacting egg production in Muscovy ducks and contributing to a decline in the abundance of Firmicutes, specifically Lactobacillus.

Spectral routing techniques have attracted plenty of research attention for the past decades, as they enable light manipulation in both the frequency domain and the spatial domain, which is crucial for applications in on-chip spectroscopy, optical switching, and modern communications. Here, we demonstrate an ultra-compact asymmetric nanoplasmonic router for communication bands that routes O and C bands to opposite positions. The nanorouter consists of two uneven grooves that create bidirectional scattered optical fields, utilizing the interference between different optical modes inside the grooves. A broadband spectrum exceeding 100 nm and a maximum extinction ratio of 31 dB are achieved, providing new opportunities for nanophotonic color routing solutions and extensions to other areas such as imaging sensors and spectral measurements.

BackgroundImplementing machine learning prediction of negative attitudes towards suicide may improve health outcomes. However, in previous studies, varied forms of negative attitudes were not adequately considered, and developed models lacked rigorous external validation. By analyzing a large-scale social media dataset (Sina Weibo), this paper aims to fully cover varied forms of negative attitudes and develop a classification model for predicting negative attitudes as a whole, and then to externally validate its performance on population and individual levels.Methods938,866 Weibo posts with relevant keywords were downloaded, including 737,849 posts updated between 2009 and 2014 (2009–2014 dataset), and 201,017 posts updated between 2015 and 2020 (2015–2020 dataset). (1) For model development, based on 10,000 randomly selected posts from 2009 to 2014 dataset, a human-based content analysis was performed to manually determine labels of each post (non-negative or negative attitudes). Then, a computer-based content analysis was conducted to automatically extract psycholinguistic features from each of the same 10,000 posts. Finally, a classification model for predicting negative attitudes was developed on selected features. (2) For model validation, on the population level, the developed model was implemented on remaining 727,849 posts from 2009 to 2014 dataset, and was externally validated by comparing proportions of negative attitudes between predicted and human-coded results. Besides, on the individual level, similar analyses were performed on 300 randomly selected posts from 2015 to 2020 dataset, and the developed model was externally validated by comparing labels of each post between predicted and actual results.ResultsFor model development, the F1 and area under ROC curve (AUC) values reached 0.93 and 0.97. For model validation, on the population level, significant differences but very small effect sizes were observed for the whole sample (χ21 = 32.35, p

Background and objectiveTo investigate the use of high-resolution magnetic resonance imaging (HR-MRI) to identify the characteristics of culprit plaques in intracranial arteries, and to evaluate the predictive value of the characteristics of culprit plaques combined with the modified Essen score for the recurrence risk of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) patients.MethodsA retrospective analysis was conducted on 180 patients with HR-NICE at the First Affiliated Hospital of Xinxiang Medical University, including 128 patients with no recurrence (non-recurrence group) and 52 patients with recurrence (recurrence group). A total of 65 patients with HR-NICE were collected from the Sixth Affiliated Hospital of Shanghai Jiaotong University as a validation group, and their modified Essen scores, high-resolution magnetic resonance vessel wall images, and clinical data were collected. The culprit plaques were analyzed using VesselExplorer2 software. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for recurrence, and a nomogram was constructed using R software to evaluate the discrimination of the model. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was used to evaluate the model performance. Calibration curves and Decision Curve Analysis (DCA) were used to evaluate the model efficacy.ResultsIntra-plaque hemorrhage (OR = 3.592, 95% CI = 1.474–9.104, p = 0.006), homocysteine (OR = 1.098, 95% CI = 1.025–1.179, p = 0.007), and normalized wall index (OR = 1.114, 95% CI = 1.027–1.222, p = 0.015) were significantly higher in the recurrent stroke group than in the non-recurrent stroke group, and were independent risk factors for recurrent stroke. The performance of the nomogram model (AUC = 0.830, 95% CI: 0.769–0.891; PR-AUC = 0.628) was better than that of the modified Essen scoring model (AUC = 0.660, 95% CI: 0.583–0.738) and the independent risk factor combination model (AUC = 0.827, 95% CI: 0.765–0.889). The nomogram model still had good model performance in the validation group (AUC = 0.785, 95% CI: 0.671–0.899), with a well-fitting calibration curve and a DCA curve indicating good net benefit efficacy for patients.ConclusionHigh-resolution vessel wall imaging combined with a modified Essen score can effectively assess the recurrence risk of HR-NICE patients, and the nomogram model can provide a reference for identifying high-risk populations with good clinical application prospects.

Background: Organophosphate esters (OPEs) and Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with common exposure sources, leading to their widespread presence in human body. However, evidence on co-exposure to OPEs and PFAS and its impact on cardiovascular-kidney-liver-metabolic biomarkers remains limited. Methods: In this cross-sectional study, 467 adults were enrolled from January to May 2022 during physical visits in Shijiazhuang, Hebei province. Eleven types of OPEs and twelves types of PFAS were detected, among which eight OPEs and six PFAS contaminants were detected in more than 60% of plasma samples. Seventeen biomarkers were assessed to comprehensively evaluate the cardiovascular-kidney-liver-metabolic function. Multiple linear regression, multipollutant models with sparse partial least squares, and Bayesian kernel machine regression (BKMR) models were applied to examine the associations of individual OPEs and PFAS and their mixtures with organ function and metabolism, respectively. Results: Of the over 400 exposure–outcome associations tested when modelling, we observed robust results across three models that perfluorohexanoic acid (PFHxS) was significantly positively associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and indirect bilirubin (IBIL). Perfluorononanoic acid was significantly associated with decreased AST/ALT and increased very-low-density lipoprotein cholesterol levels. Besides, perfluorodecanoic acid was correlated with increased high lipoprotein cholesterol and perfluoroundecanoic acid was consistently associated with lower glucose level. BKMR analysis showed that OPEs and PFAS mixtures were positively associated with IBIL and TBIL, among which PFHxS was the main toxic chemicals. Conclusions: Our findings suggest that exposure to OPEs and PFAS, especially PFHxS and PFNA, may disrupt organ function and metabolism in the general population, providing insight into the potential pathophysiological mechanisms of OPEs and PFAS co-exposure and chronic diseases.

Summary: Positive autoregulation (PAR), one type of network motifs, provides a high phenotypic heterogeneity for cells to better adapt to their microenvironments. Typical mechanosensitive proteins can also form PAR, e.g., integrin mediated PAR, but the role of such mechanical PAR in physiological development and pathological process remains elusive. In this study, we found that transforming growth factor β1 (TGF-β1) and integrin levels decrease with tissue softening after the development of paradentium in vivo in rat model of periodontitis (an inflammatory disease with bone defect). Interestingly, TGF-β1 could induce the formation of mechanical PAR involving the integrin-FAK-YAP axis in mesenchymal stem cells (MSCs) by both in vitro experiments and in silico computational model. The computational model predicted a mechanical PAR involving the bimodal distribution of focus adhesions, which enables cells to accurately perceive extracellular mechanical cues. Thus, our analysis of TGF-β1 mediated mechanosensing mechanism on MSCs may help to better understand the molecular process underlying bone regeneration.

ABSTRACT: Mule ducks tend to accumulate abundant fat in their livers via feeding, which leads to the formation of a fatty liver that is several times larger than a normal liver. However, the mechanism underlying fatty liver formation has not yet been elucidated. Fibroblast growth factor 1 (FGF1), a member of the FGF superfamily, is involved in cellular lipid metabolism and mitosis. This study aims to investigate the regulatory effect of FGF1 on lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells and elucidate the underlying molecular mechanism. Hepatocytes were induced by adding 1,500:750 µmol/L oleic and palmitic acid concentrations for 36 h, which were stimulated with FGF1 concentrations of 0, 10, 100, and 1000 ng/mL for 12 h. The results showed that FGF1 significantly reduced the hepatic lipid droplet deposition and triglyceride content induced by complex fatty acids; it also reduced oxidative stress; decreased reactive oxygen species fluorescence intensity and malondialdehyde content; upregulated the expression of antioxidant factors nuclear factor erythroid 2 related factor 2 (Nrf2), HO-1, and NQO-1; significantly enhanced liver cell activity; promoted cell cycle progression; inhibited cell apoptosis; upregulated cyclin-dependent kinase 1 (CDK1) and BCL-2 mRNA expression; and downregulated Bax and Caspase-3 expression. In addition, FGF1 promoted AMPK phosphorylation, activated the AMPK pathway, upregulated AMPK gene expression, and downregulated the expression of SREBP1 and ACC1 genes, thereby alleviating excessive fat accumulation in liver cells induced by complex fatty acids. In summary, FGF1 may alleviate lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells by activating the AMPK signaling pathway.

Abstract Parkinson's disease (PD) is a mitochondria‐related neurodegenerative disease characterized by locomotor deficits and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Majority of PD research primarily focused on neuronal dysfunction, while the roles of astrocytes and their mitochondria remain largely unexplored. To bridge the gap and investigate the roles of astrocytic mitochondria in PD progression, we constructed a specialized optogenetic tool, mitochondrial‐targeted anion channelrhodopsin, to manipulate mitochondrial membrane potential in astrocytes. Utilizing this tool, the depolarization of astrocytic mitochondria within the SNc in vivo led to the accumulation of γ‐aminobutyric acid (GABA) and glutamate in SNc, subsequently resulting in excitatory/inhibitory imbalance and locomotor deficits. Consequently, in vivo calcium imaging and interventions of neurotransmitter antagonists demonstrated that GABA accumulation mediated movement deficits of mice. Furthermore, 1 h/day intermittent astrocytic mitochondrial depolarization for 2 weeks triggered spontaneous locomotor dysfunction, α‐synuclein aggregation, and the loss of DA neurons, suggesting that astrocytic mitochondrial depolarization was sufficient to induce a PD‐like phenotype. In summary, our findings suggest the maintenance of proper astrocytic mitochondrial function and the reinstatement of a balanced neurotransmitter profile may provide a new angle for mitigating neuronal dysfunction during the initial phases of PD.

Intervertebral disc degeneration (IDD) is widely recognized as the primary culprit of chronic low back pain. Restoring deteriorated intervertebral disc (IVD) and alleviating IDD‐induced low back pain are remaining enormous challenges. There is a genetic susceptibility to IDD, and gene therapy has some therapeutic potential. However, traditional gene therapy still has certain drawbacks, including host immunity, temporary release, and suppression of gene medication function. Although regenerative materials can effectively improve the local microenvironment, they cannot treat IDD from the root. Gene‐functionalized regenerative material (GRM) is constructed based on physical embedding or forming chemical bonds by introducing particular genes, such as pDNA, siRNA, mRNA, and miRNA, into the regenerated materials. The findings demonstrate that GRM not only enhances the safety and controllability of gene therapy, but also effectively repairs IDD by overcoming the constraint that simple regenerative materials cannot reverse the disease's progression from the root. This article provided a brief overview of the physiological and pathological features of the IVD, genetic susceptibility to IDD, available treatment options, and their limitations. Then, the significance of GRM‐based treatment of IDD is proposed, and the future challenges and development in this field are finally prospected.