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Abstract The traditional diagnostic markers for mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are synaptophysin (SYP), chromogranin A (CHGA) and CD56. However, there is still a lack of a large series of article focused on the expression of insulinoma-associated protein 1 (INSM1) in gastrointestinal and pancreatic MiNENs. This study compared the expression of INSM1 and traditional neuroendocrine markers in MiNENs. In this study, we collected 46 cases of gastrointestinal and pancreatic MiNENs and performed immunohistochemical staining for INSM1, SYP, CHGA, and CD56. Histologically, the neuroendocrine components of MiNENs were all neuroendocrine carcinomas, with small cell neuroendocrine carcinomas accounting for 15.2% (7/46) and large cell neuroendocrine carcinomas accounting for 84.8% (39/46). With respect to immunohistochemical expression, the overall sensitivity of INSM1 was 80.4% (37/46), which was lower than that of SYP (100%, 46/46), but comparable to that of CHGA (67.4%, 31/46) or CD56 (73.9%, 34/46). The overall specificity of INSM1 was 91.3% (42/46), which was greater than that of SYP (63.0%, 29/46) and CD56 (69.6, 32/46), but was not significantly different from that of CHGA (82.6%, 38/46). The proportion of 3 + staining for SYP (100%, 46/46) was greater than that of INSM1 (71.7, 33/46), while the proportion of 3 + staining for CHGA (10.9, 5/46) or CD56 (21.7, 10/46) was lower than that of INSM1. In conclusion, INSM1 exhibited high sensitivity and specificity in the diagnosis of gastrointestinal and pancreatic MiNENs.

Abstract Arterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptor–ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbβ3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patient’s pathological profile.

Abstract Metal nanoparticles have extraordinary properties, but their integration into mesostructures has been challenging. Producing uniformly dispersed nanoparticles attached to substrates in industrial quantities is difficult. Herein, a “plasmashock” method was developed to synthesize metal nanoparticles anchored on different types of carbonaceous substrates using liquid salt solution precursors. These self-supporting, nanoparticle-loaded carbon fabrics are mechanically robust and have been tested as antibacterial substrates and electrocatalysts for reducing carbon dioxide and nitrite. A piece of silver–carbon nanotube paper with a silver loading of ~0.13 mg cm−2 treated after a few-second plasmashock presents good antibacterial and electrocatalytic properties in wastewater, even after 20 bactericidal immersion cycles, due to the strong bonding of the nanoparticles to the substrate. The results prove the effectiveness of this plasmashock method in creating free-standing functional composite films or membranes.

Abstract Background Insect-based food and feed are increasingly attracting attention. As a domesticated insect, the silkworm (Bombyx mori) has a highly nutritious pupa that can be easily raised in large quantities through large-scale farming, making it a highly promising source of food. The ratio of pupa to cocoon (RPC) refers to the proportion of the weight of the cocoon that is attributed to pupae, and is of significant value for edible utilization, as a higher RPC means a higher ratio of conversion of mulberry leaves to pupa. In silkworm production, there is a trade-off between RPC and cocoon shell ratiao(CSR), which refers the ratio of silk protein to the entire cocoon, during metamorphosis process. Understanding the genetic basis of this balance is crucial for breeding edible strains with a high RPC and further advancing its use as feed. Results Using QTL-seq, we identified a quantitative trait locus (QTL) for the balance between RPC and CSR that is located on chromosome 11 and covers a 9,773,115-bp region. This locus is an artificial selection hot spot that contains ten non-overlapping genomic regions under selection that were involved in the domestication and genetic breeding processes. These regions include 17 genes, nine of which are highly expressed in the silk gland, which is a vital component in the trade-off between RPC and CSR. These genes are annotate with function related with epigenetic modifications and the regulation of DNA replication et al. We identified one and two single nucleotide polymorphisms (SNPs) in the exons of teh KWMTBOMO06541 and KWMTBOMO06485 genes that result in amino acid changes in the protein domains. These SNPs have been strongly selected for during the domestication process. The KWMTBOMO06485 gene encodes the Bombyx mori (Bm) tRNA methyltransferase (BmDnmt2) and its knockout results in a significant change in the trade-off between CSR and RPC in both sexes. Conclusions Taken together, our results contribute to a better understanding of the genetic basis of RPC and CSR. The identified QTL and genes that affect RPC can be used for marker-assisted and genomic selection of silkworm strains with a high RPC. This will further enhance the production efficiency of silkworms and of closely-related insects for edible and feed purposes.

The keyhole phenomenon, frequently found in LPBF, is critically responsible for the formation of internal porosities which degrades the part quality. Owing to the ultra-high transience and complexity of the LPBF process, the underlying mechanisms during the keyholing process have not been well understood. In this work, a Multiphysics-based CFD model is developed to simulate the keyhole-penetration process in LPBF of CuCrZr alloy, and the ray-tracing laser heat source is implemented to visualize the multiple laser reflections. The simulation results are well validated in terms of the track size, porosity distribution and laser absorption by conducting the single-track experiment, X-CT scanning and calorimetric measurement, respectively. The flow patterns, driving forces and laser irradiation behaviors in the keyhole mode are collectively elucidated to understand the formation mechanisms of the keyhole-induced pores. The reduction of laser ray entries into the emerging cavity with a shrinking opening is noticed and contributes to the pore formation.

Abstract Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.

Abstract TP53 mutation (TP53-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for TP53-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had TP53-mut. Since missense mutations account for the vast majority of TP53-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A TP53 missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of TP53-mut DLBCL, we combined clinical characteristics and ultimately constructed the TP53 Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk TP53-mut DLBCL patients and explained this difference at the mutation and transcriptional levels.

Abstract Background The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) serves as a novel composite lipid indicator for atherosclerosis. However, the association between NHHR and mortality in patients with diabetes or prediabetes remains unclear. Consequently, the objective of this study was to investigate the relationship between NHHR and both all-cause and cardiovascular mortality in US adults with diabetes or prediabetes. Methods This study included 12,578 adult participants with diabetes or prediabetes from the US National Health and Nutrition Examination Survey (1999–2018). Mortality outcomes were ascertained by linking to the National Death Index (NDI) record up to December 31, 2019. We employed a weighted multivariate Cox proportional hazards model and restricted cubic splines to assess the associations between NHHR and all-cause and cardiovascular mortality. A segmented Cox proportional hazards model was used for evaluating threshold effects. Furthermore, a competing risks analysis was performed to explore the relationship between NHHR and cardiovascular mortality. Results During a median follow-up period of 8.08 years, 2403 participants encountered all-cause mortality, with 662 of them specifically succumbing to cardiovascular mortality. The restricted cubic splines revealed a U-shaped association between NHHR and all-cause mortality, while an L-shaped association was observed for cardiovascular mortality. The analysis of threshold effects revealed that the inflection points for NHHR and all-cause and cardiovascular mortality were 2.72 and 2.83, respectively. Specifically, when the baseline NHHR was below the inflection points, a negative correlation was observed between NHHR and both all-cause mortality (HR: 0.76, 95% CI: 0.68–0.85) and cardiovascular mortality (HR: 0.70, 95% CI: 0.57–0.85). Conversely, when the baseline NHHR exceeded the inflection points, a positive correlation was observed between NHHR and both all-cause mortality (HR: 1.11, 95% CI: 1.06–1.16) and cardiovascular mortality (HR: 1.08, 95% CI: 1.00–1.16). Conclusions Among US adults with diabetes or prediabetes, a U-shaped association was observed between NHHR and all-cause mortality, whereas an L-shaped association was identified with cardiovascular mortality. The inflection points for all-cause and cardiovascular mortality were 2.72 and 2.83, respectively.

Abstract Ceramic cutting inserts are a type of cutting tool commonly used in high-speed metal cutting applications. However, the wear of these inserts caused by friction between the workpiece and cutting inserts limits their overall effectiveness. In order to improve the tool life and reduce wear, this study introduces an emerging method called magnetic field-assisted batch polishing (MABP) for simultaneously polishing multiple ceramic cutting inserts. Several polishing experiments were conducted under different conditions, and the wear characteristics were clarified by cutting S136H steel. The results showed that after 15 min of polishing, the surface roughness at the flank face, edge, and nose of the inserts was reduced to below 2.5 nm, 6.25 nm, and 45.8 nm, respectively. Furthermore, the nose radii of the inserts did not change significantly, and there were no significant changes in the weight percentage of elements before and after polishing. Additionally, the tool life of the batch polished inserts was found to be up to 1.75 times longer than that of unpolished inserts. These findings suggest that the MABP method is an effective way to mass polish ceramic cutting inserts, resulting in significantly reduced tool wear. Furthermore, this novel method offers new possibilities for polishing other tools.

CrMnFeCoNi high-entropy alloy (HEA) manufactured by laser powder bed fusion has been demonstrated to possess a superior trade-off of tensile strength and ductility due to unique microstructures during the printed process. However, the improvement of mechanical properties of 3D printed-CrMnFeCoNi HEA through the addition of nano-scaled ceramic particles instead of in-situ precipitated particles is poorly studied. In this work, the effects of WC additions on the microstructure evolution and strengthening mechanism of additive-manufactured HEA samples at both room temperature (298 K) and cryogenic temperature (77 K) were systematically investigated. Except for the representative hierarchical microstructure characteristics of 3D printed- HEA samples, WC particles are dissolved completely in the CrMnFeCoNi matrix without obvious element segregation. The mechanical tests at room temperature (RT) revealed an excellent comprehensive mechanical property (tensile strength of 925 MPa and ductility of 38%) of the HEA sample with 5 wt% WC addition, which is mainly attributed to the solid solution strengthening induced by WC dissolution. In addition, the strength and ductility of the HEA sample synchronously increase when the testing temperature decreases from 298 K to 77 K, due to the reaction between dislocation and high-density deformation twins (DTs). The tensile strength (∼1420 MPa) of HEA-5 wt% WC sample at 77 K is higher than that of traditional CrMnFeCoNi HEA, because of contribution to strengthening from dislocation pile-up, entanglement and wavy dislocation slide.

Objective There is a strong relationship between the content of beneficial fatty acids in milk and milk fat metabolic activity in the mammary gland. To improve milk quality, it is therefore necessary to study fatty acid metabolism in bovine mammary gland tissue. In adipose tissue, peroxisome proliferator-activated receptor gamma (PPARG), the core transcription factor, regulates the fatty acid metabolism gene network and determines fatty acid deposition. However, its regulatory effects on mammary gland fatty acid metabolism during lactation have rarely been reported. Methods Transcriptome sequencing was performed during the prelactation period and the peak lactation period to examine mRNA expression. The significant upregulation of PPARG drew our attention and led us to conduct further research. Results According to bioinformatics prediction, dual-luciferase reporter system detection, real-time quantitative reverse transcription polymerase chain reaction and Western blotting, miR-130a and miR-130b could directly target PPARG and inhibit its expression. Furthermore, triglyceride and oil red O staining proved that miR-130a and miR-130b inhibited milk fat metabolism in bovine mammary epithelial cells (BMECs), while PPARG promoted this metabolism. In addition, we also found that the coexpression of miR-130a and miR-130b significantly enhanced their ability to regulate milk fat metabolism. Conclusion In conclusion, our findings indicated that miR-130a and miR-130b could target and repress PPARG and that they also have a functional superposition effect. miR-130a and miR-130b seem to synergistically regulate lipid catabolism via the control of PPARG in BMECs. In the long-term, these findings might be helpful in developing practical means to improve high-quality milk.

The composition and concentration of volatile organic compounds (VOCs) in exhaled breath are closely related to human health and the analysis of VOCs by collecting human exhaled breath has been widely used in disease surveillance research. This article reviewed the collection, enrichment, and detection methods of exhaled VOCs, which can provide a reference for selecting appropriate technology for follow-up research. The exhaled breath collection devices mainly include sampling bags for mixed exhaled breath and biological volatile organic compound (Bio-VOC) samplers for alveolar air. The pre-enrichment equipment included thermal desorption (TD), solid-phase microextraction device (SPME), and needle trap device (NTD). The detection methods of exhaled VOCs include gas chromatography-mass spectrometry (GC-MS), proton transfer reaction mass spectrometry (PTR-MS), selective ion flow tube mass spectrometry (SIFT-MS), and electronic nose. At present, the collection and enrichment technology of exhaled breath is not mature yet, and its influence on the results of detection is lack of evaluation. In the future, the research on collection and enrichment technology of exhaled breath should be strengthened to further promote the application of exhaled breath in disease surveillance research.

BackgroundStroke is one of the major chronic non-communicable diseases (NCDs) with high morbidity, disability and mortality. The key to preventing stroke lies in controlling risk factors. However, screening risk factors and quantifying stroke risk levels remain challenging.MethodsA novel prediction model for stroke risk based on two-level feature selection and deep fusion network (SRPNet) is proposed to solve the problem mentioned above. First, the two-level feature selection method is used to screen comprehensive features related to stroke risk, enabling accurate identification of significant risk factors while eliminating redundant information. Next, the deep fusion network integrating Transformer and fully connected neural network (FCN) is utilized to establish the risk prediction model SRPNet for stroke patients.ResultsWe evaluate the performance of the SRPNet using screening data from the China Stroke Data Center (CSDC), and further validate its effectiveness with census data on stroke collected in affiliated hospital of Jining Medical University. The experimental results demonstrate that the SRPNet model selects features closely related to stroke and achieves superior risk prediction performance over benchmark methods.ConclusionsSRPNet can rapidly identify high-quality stroke risk factors, improve the accuracy of stroke prediction, and provide a powerful tool for clinical diagnosis.

Background: Exposed, infected and necrotic tendons often occur in the middle and late stages of diabetic foot ulcers (DFUs). The exposed tendon is both a potential source and route of infection, which prolongs the treatment period and affects recovery, leading to amputation and even death. Therefore, management of the exposed tendon in patients with DFU is the key to treatment. This study aimed to evaluate the clinical efficacy of Shengji ointment combined with bromelain in the treatment of DFU with tendon exposure and to provide clinical treatment options and evidence-based medicine. Methods: This study was a multicenter, nonblinded, randomized, positive controlled clinical trial involving 180 patients with DFU with tendon exposure at four tertiary-grade A-class hospitals. The included patients were randomly assigned 1:1 to an observation group (n = 90) that received Shengji ointment combined with bromelain and a control group (n = 90) that received hydrocolloid dressing, with dressing changes once daily for 4 weeks. Patients in both groups continued with conventional treatments, such as blood glucose and blood pressure medication, lipid regulation, and antiplatelets. The primary outcome measure was wound coverage with granulation tissue. The secondary outcome measures included the wound healing rate, time to granulation, Maryland foot score, time to debridement of necrotic tendon tissue, and granulation tissue score. We performed measurements before enrollment and after the end of treatment for comparison. Results: There was no significant difference in the baseline data between the two groups before treatment (P > 0.05). After treatment, the primary outcome indicators of the two groups were compared, and the wound granulation tissue coverage rate of the treatment group was greater than that of the control group (P = 0.003). For the secondary outcome outcomes, the wound healing rate, time to granulation, Maryland foot function score, time to debridement of necrotic tendon tissue, and granulation tissue score in the treatment group were significantly better than those in the control group (P

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

IntroductionTo ensure higher productivity, fertilizers have been excessively applied to the fruit greenhouse soil yearly, thus resulting in the increasing risks of residual nitrate leaching in the North China Plain.MethodsIn this study, a water and solute transport HYDRUS-1D model was used to evaluate the effects of using sweet corn as a catch crop on deep water drainage and nitrate leaching in a sweet cherry greenhouse soil. A three-year (2019–2021) field experiment was conducted during the rainfall season from July to September in the post-harvest of sweet cherry, when the plastic cover was removed each year. In the experiment, the five treatments were designed. The three nitrate residue levels denoted by CKR, N1R, and N2R, represented nitrate residue amounts in the soil profile of three nitrogen fertilizer levels(0, 280 and 420kg ha-1) before the harvest of sweet cherry(March to June). Two other treatments with and without sweet corn as a catch crop based on the treatments of N1R and N2R were denoted by N1RC and N2RC, respectively. The data of both the spatial and temporal distribution of water and nitrate content during the rainy seasons of 2019, 2020 and 2021 in the field experiment were collected to calibrate and validate the model. ResultsThe simulated results have showed that using sweet corn as a catch crop increased the evapotranspiration rate, the upward flux of water and nitrate at a 100 cm soil depth reached a maximum of 1.5 mm d-1 and 1.0 kg N ha-1d-1, respectively, and the downward movement of water and nitrate leached to deeper soil layers was reduced. Compared with CKR, the treatments with catch crops (N1RC and N2RC) reduced the amount of water drainage by 16.4% -47.7% in the 0-180cm soil profile. The average amounts of nitrate leaching in the 1.8 m soil profile during the three-year experiment were 88.1, 113.3, and 58.2 kg N ha−1 for the treatment without catch crop (N1R and N2R) and 32.3, 54.8, and 31.4 kg N ha−1 for the treatment with catch crop (N1RC and N2RC), respectively. The treatments (N1RC and N2RC) with catch crops decreased the amount of nitrate leaching by 29.6%-69.1% compared with the treatments without catch crops (N1R and N2R).DiscussionSweet corn as summer catch crop can reduce nitrate leaching in the sweet cherry greenhouses. Our study has provided an effective method to reduce the risk of nitrate leaching for sweet cherry greenhouses in the North China Plain.

Objectives: To analyze the methodology, evidence, recommendations, quality, and implementation of traditional Chinese patent medicine (CPM) guidelines. Methods: We retrieved clinical application guidelines of CPM published from 2019 to 2022. Independent screening and data extraction were performed by two evaluators. The basic information about the guidelines, including evidence and recommendations, were extracted and statistically analyzed. Quality and implementation were evaluated using the Implementation Evaluation Tool and Appraisal of Guidelines for Research & Evaluation (AGREE) II. Results: In total, 29 guidelines were analyzed, including 262 recommendations and 2308 references. All the CPM guidelines followed the principle of “evidence as a core, consensus as a supplement, and experience as a reference'' and the methods provided by WHO Handbook. An average of 89 references were cited in each guideline and 8 in each recommendation. Randomized controlled trials and systematic reviews constituted 89 % and 0.9 %, respectively, of all references. Low or very low-quality evidence characterized 74.5 % and weak recommendations characterized 83.6 %. Of all recommendations, 13.7 % were based on expert consensus, and 9.5 % of strong recommendations were based on low or very low-quality evidence. The AGREE II scores for each domain were: scope and purpose (79.63 %) and editorial independence (79.27 %), followed by clarity of presentation (72.59 %), stakeholder involvement (69.99 %), rigor of development (53.97 %) and applicability (5.11 %). The implementation quality of most guidelines was either high (44.8 %) or moderate (55.2 %). Conclusions: The results for CPM guidelines were impressive in terms of methodology, quality, and implementation. However, confidence in CPM recommendations was downgraded by low quality of evidence.

BackgroundPostoperative patients with primary hepatocellular carcinoma (HCC) confront not only physiological challenges but also psychological and social adaptation issues. It is imperative to enhance psycho-social adjustment (PSA) levels and further improve the quality of life among this population. However, research on PSA levels in postoperative HCC patients is lacking, and investigations into its associations with psychological resilience, social support, and fear of progression (FoP) remain unexplored currently.ObjectivesThis study aims to: (1) investigate the current status of PSA and analyze its influencing factors among postoperative HCC patients; (2) explore the interrelationships among psychological resilience, social support, FoP and PSA based on the Chronic Illness Adaptation Model employing a structural equation model.MethodsConvenience sampling methods were employed to recruit participants from the Department of Hepatobiliary Surgery at a tertiary hospital in Xi’an, Shaanxi, China, and a total of 399 patients completed the surveys. The survey instruments included a general information questionnaire, Connor-Davidson Resilience Scale (CD-RISC), Social Support Rating Scale (SSRS), Fear of Progression Questionnaire-Short Form (FoP-Q-SF), and Psychosocial Adjustment to Illness Scale Self-report (PAIS-SR). Data entry was conducted using Epidata 3.1 with dual verification, followed by statistical analyses performed using SPSS 27.0 and Amos 28.0.ResultsThe structural equation model revealed two paths. In Path 1 (psychological resilience → FoP → PSA), the direct effect was −0.383 (95% CI [−0.589, −0.112]), with an indirect effect of −0.075 (95% CI [−0.170, −0.018]). In Path 2 (social support → FoP → PSA), the direct effect was −0.297 (95% CI [−0.587, −0.063]), with an indirect effect of −0.069 (95% CI [−0.156, −0.019]).ConclusionPostoperative patients with primary HCC exhibit lower levels of PSA. Higher levels of psychological resilience and social support correspond to elevated PSA levels. Conversely, advanced age, greater financial burden, and increased FoP are associated with lower PSA levels. FoP serves as a partial mediator between psychological resilience and PSA, as well as between social support and PSA. Future research would benefit from longitudinal designs to elucidate the developmental trajectories and causal links among these variables.

The Rongcheng High, located on the center of the Jizhong Depression, North China, presents favorable geothermal and geological characteristics, thereby rendering the fine subsurface structure crucial for accurately assessing seismic hazards and the potential for geothermal resources. In 2019, a recently acquired three-dimensional (3D) seismic dataset and processing methodologies were introduced to generate a high-resolution seismic reflection volume, centered on the Rongcheng High. The 3D reflection data revealed numerous prominent reflectors and associated fault structures, enabling a detailed study of the subsurface structure and providing an insight into the structural evolution of the Cenozoic Rongcheng High. A dissection of the fault system in the Rongcheng High unveiled a complex geometry characterized by both shallow and deep faults, indicating an initial phase of extension, followed by subsequent dextral strike-slip displacement. The Rongcheng Fault delineates the boundary between the Rongcheng High and Xushui Sag, influencing the fault sag and facilitating the development of a larger accommodation space. The depositional center shifted from west to east. The faults in the Cenozoic exhibited varying patterns of activity, beginning frequently in early Paleogene, followed by a decline, ultimately culminating in Neogene. The study area experienced two uplift events at the end of Ek2 (Kongdian-2 Formation) and Ed (Dongying Formation), resulting in the complete denudation of the Sha-2 and Dongying formations. A structural pattern characterized by alternating high and sag areas in the study area was established at the end of the depositional period of the Dongying Formation.

BackgroundThe escalating global economic burden of ischemic stroke poses a significant public health challenge amid global aging trends. The broad therapeutic efficacy of new antidiabetic drugs may offer new options in the prevention and treatment of ischemic stroke. Consistent conclusions regarding the relationship between novel antidiabetic agents and the risk of ischemic stroke remain elusive, and the causal relationship deserves further investigation.Materials and methodsThree novel antidiabetic drug targets were selected, and cis-expression quantitative trait loci (cis-eQTL) were screened as instrumental variables. Genetic association data for ischemic stroke were obtained from the Genome-wide Association Study (GWAS) database. Mendelian randomization (MR) analysis, facilitated by R software, calculated MR estimates for each single nucleotide polymorphism (SNP), and meta-analysis was performed using five methods. To ensure robustness, sensitivity analyses, heterogeneity analyses, horizontal pleiotropy analyses, and co-localization analyses were conducted for significant MR associations.ResultsThree eQTLs for antidiabetic drug genes served as instrumental variables, utilizing a GWAS dataset comprising 34,217 cases and 406,111 controls for ischemic stroke. Genetic variants in glucagon-like peptide-1 receptor agonists (GLP-1 RA) targets exhibited a positive correlation with ischemic stroke risk (OR 1.06, 95% CI 1.04–1.08, P = 0.000), while genetic variation in dipeptidyl peptidase 4 inhibitors (DPP-4i) targets showed a negative association with ischemic stroke risk (OR 0.93, 95% CI 0.89–0.97, P = 0.003). Sensitivity analyses supported robust conclusions, revealing no heterogeneity or horizontal pleiotropy.ConclusionThis study found that GLP-1 RA and DPP-4i were associated with an increased risk of ischemic stroke by MR analysis. Although sensitivity analyses provide support for this result, it contradicts previous knowledge. Therefore, the results of this study still need to treated with caution. Updated and more in-depth GWAS data and high-quality real-world data are expected to validate the results.

As two important greenhouse gases in the atmosphere, CO2 and N2O have been paid much attention to their environmental effects. As a large agricultural and population country in the world, agricultural soil is an important source of greenhouse gas emissions. In recent years, unreasonable agricultural measures will make the soil structure deteriorate and lead to the increase of saline-alkali cultivated land area. Therefore, the comprehensive utilization of saline-alkali land has practical significance for agricultural production and ecological environment safety in our country. In this study, the 11th Regiment of Alar City of the First Division of Xinjiang carried out field tests on saline-alkali cultivated land, and improved the saline-alkali cultivated land with desulfurized gypsum and aeolian sand. Six treatments were set up (blank treatment (CK) desulfurized gypsum 15 t/ha (LH), desulfurized gypsum 30 t/ha (LA), desulfurized gypsum 15 t/hamixed application (FL), Aeolian sand 15 t/ha (FH), and Aeolian sand 30 t/ha (FA)). The effects of different treatments on CO2 and N2O emission fluxes in cotton-pepper soil were observed. The results show that: (1) In the growth stage of cotton-pepper, compared with CK, soil moisture increased, and soil ammonium nitrogen decreased; The conductivity increases with the increase of desulphurized gypsum and the decrease of aeolian sand. The results showed that LA treatment had the best water retention effect and FA treatment had the best salt reduction effect. (2) Compared with CK, the cumulative CO2 emission fluxes of cotton soil under different treatments were CK > LH > FL > FH > LA > FA treatment, and those of pepper soil were CK > FL > LH > FH > FA > LA treatment. Among them, the inhibition effect of cumulative soil CO2 emission under LA and FA treatment reached a significant level. (3) Compared with CK, the cumulative N2O emission fluxes of LH, LA, FL, FH and FA treated soil in cotton field were CK > LA > LH > FH > FL > FA, and that of pepper soil was CK > FA > LH > LA > FL > FH. Among them, the inhibition effect of aeolian sand (FA and FH) on soil N2O cumulative emission reached a significant level. (4) Compared with CK, LH, LA, FL, FH and FA treatments reduced the comprehensive greenhouse effect of cotton field and pepper crops by inhibiting soil CO2 emission fluxes, among which FA treatment had the lowest comprehensive greenhouse effect. Therefore, the effects of different treatments on physicochemical properties and gas emissions of saline-alkali soil were comprehensively analyzed, and FA treatment had the best effect on inhibiting CO2 and N2O emissions and improving soil physicochemical properties.

Abstract Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single‐cell RNA sequencing (scRNA‐seq) on diethylnitrosamine (DEN)‐induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor‐associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA‐seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.

Hydraulic fracturing is an important technical means to relieve the pressure of coal seam roof. Better understanding of fracture propagation mechanism is of great significance to the safe mining of coal seam. In order to further explore the law of hydraulic fracture propagation, aiming at rock-like specimens commonly used in the laboratory, MatDEM, a particle discrete element numerical simulation software, was used to establish a two-dimensional discrete element numerical model of hydraulic fracturing, and various hydraulic fracturing tests with different injection pressure increments were carried out. The effect of injection pressure increment on the propagation of hydraulic fractures was studied, and the mechanism of model initiation was revealed. The law of fracture generation and propagation was analyzed from mesoscale, and the propagation characteristics of hydraulic fractures were discussed. The results show that ① the effect of injection pressure increment on the model initiation pressure and initiation time presents an opposite trend. With the increase of injection pressure, the increase trend of initiation pressure is slow and gradually approaches to 5.6 MPa. The initiation time decreases with the increase of injection pressure, and the decreasing trend slows down gradually. ② The cumulative number of fractures increases exponentially with time. The hydraulic fracturing process can be divided into four stages (Ⅰ−Ⅳ): no fracture stage, slow fracture growth stage, steady fracture growth stage and rapid fracture growth stage, which correspond to the pre-crack initiation, pre-crack formation, primary fracture propagation and secondary fracture propagation processes respectively. As the injection pressure increment increases, the durations of stage Ⅰ, Ⅱ and Ⅲ decrease, while the duration of stage Ⅳ increases in a fluctuating manner. The number of cracks in each stage is the highest in stage Ⅳ, followed by stage Ⅲ and stage Ⅱ. ③ As the injection pressure increment increases, the number of secondary fractures increases from 8 to 16, and the growth rate of fractures gradually slows down before the stage Ⅲ, and increases rapidly after the stage Ⅳ. When the injection pressure increment increases from 0.03 MPa to 0.70 MPa, the final fracture length increases by 1.79 times. ④ The internal energy of the model increases with the increase of the injection pressure increment, and the energy input speed gradually becomes faster. After the model initiation, high-pressure water forms stress concentration at the crack tip, which promotes the crack to continue to extend. At higher injection pressure increment, the fracture propagation speed becomes faster, and the particle displacement decreases gradually from the pressure hole to the outside of the model. The increment of injection pressure makes the secondary fracture forming position close to the pressure hole, which inhibits the formation and expansion of the primary fracture and promotes the formation and expansion of the secondary fracture. All fracture types are tensile fractures.

Abstract To compare and analyze the diagnostic value of different enhancement stages in distinguishing low and high nuclear grade clear cell renal cell carcinoma (ccRCC) based on enhanced computed tomography (CT) images by building machine learning classifiers. A total of 51 patients (Dateset1, including 41 low-grade and 10 high-grade) and 27 patients (Independent Dateset2, including 16 low-grade and 11 high-grade) with pathologically proven ccRCC were enrolled in this retrospective study. Radiomic features were extracted from the corticomedullary phase (CMP), nephrographic phase (NP), and excretory phase (EP) CT images, and selected using the recursive feature elimination cross-validation (RFECV) algorithm, the group differences were assessed using T-test and Mann–Whitney U test for continuous variables. The support vector machine (SVM), random forest (RF), XGBoost (XGB), VGG11, ResNet18, and GoogLeNet classifiers are established to distinguish low-grade and high-grade ccRCC. The classifiers based on CT images of NP (Dateset1, RF: AUC = 0.82 ± 0.05, ResNet18: AUC = 0.81 ± 0.02; Dateset2, XGB: AUC = 0.95 ± 0.02, ResNet18: AUC = 0.87 ± 0.07) obtained the best performance and robustness in distinguishing low-grade and high-grade ccRCC, while the EP-based classifier performance in poorer results. The CT images of enhanced phase NP had the best performance in diagnosing low and high nuclear grade ccRCC. Firstorder_Kurtosis and firstorder_90Percentile feature play a vital role in the classification task.

Abstract Background Previous studies on whole grain consumption had inconsistent findings and lacked quantitative assessments of evidence quality. Therefore, we aimed to summarize updated findings using the Burden of Proof analysis (BPRF) to investigate the relationship of whole grain consumption on type 2 diabetes (T2D), colorectal cancer (CRC), stroke, and ischemic heart disease (IHD). Methods We conducted a literature search in the Medline and Web of Science up to June 12, 2023, to identify related cohort studies and systematic reviews. The mean RR (relative risk) curve and uncertainty intervals (UIs), BPRF function, risk-outcome score (ROS), and the theoretical minimum risk exposure level (TMREL) were estimated to evaluate the level of four risk-outcome pairs. Results In total, 27 prospective cohorts were included in our analysis. Consuming whole grain at the range of TMREL (118.5–148.1 g per day) was associated with lower risks: T2D (declined by 37.3%, 95% UI: 5.8 to 59.5), CRC (declined by 17.3%, 6.5 to 27.7), stroke (declined by 21.8%, 7.3 to 35.1), and IHD (declined by 36.9%, 7.1 to 58.0). For all outcomes except stroke, we observed a non-linear, monotonic decrease as whole grain consumption increased; For stroke, it followed a J-shaped curve (the greatest decline in the risk of stroke at consuming 100 g whole grain for a day). The relationships between whole grain consumption and four diseases are all two-star pairs (ROS: 0.087, 0.068, 0.062, 0.095 for T2D, CRC, stroke, and IHD, respectively). Conclusion Consuming 100 g of whole grains per day offers broad protective benefits. However, exceeding this threshold may diminish the protective effects against stroke. Our findings endorse replacing refined grains with whole grains as the main source of daily carbohydrates. Registry and registry number for systematic reviews or meta-analyses We have registered our research in PROSPERO, and the identifier of our meta-analyses is CRD42023447345.

As a cell proliferation regulator involved in wide biological processes in plants, GRF-INTERACTING FACTOR (GIF) controls different tissues development. However, whether GIF participates in fruit development remains unclear. According to transcriptome data, we identified PbGIF1 was highly expressed during fruit development in cytokinins induced parthenocarpy pear. In the present study, the biofunction of PbGIF1 was initially verified. Overexpression of PbGIF1 promoted fruit size of transgenic tomato. The size of flesh fruit was not affected by cell expansion but the cell proliferation was promoted by overexpressing PbGIF1. The accelerated cell proliferation process was also observed in PbGIF1-overexpressed transgenic pear fruit calli. The transcriptional regulation of cytokinins on PbGIF1 was further confirmed by exogenous CPPU treatments in pear fruitlets. To investigate the underlying mechanism, the cytokinins-responded factor, PbRR1, was further focused on. The results of Yeast-one-hybrid assay suggested that PbRR1 can bind to the promoter sequence of PbGIF1. The transcriptional activation of PbRR1 on PbGIF1 was also confirmed by Dual-Luciferase assays. Taken together, the results showed that cytokinins control pear fruit development via the transcriptional activation of PbGIF1 by PbRR1.

In this study, a series of austempering treatments were carried out on the designed novel 60Si2CrVNb spring steel and the effects of different austempering temperatures on the microstructure and mechanical properties of the steel were studied. The results show that after austempering treatments, the microstructure of 60Si2CrVNb spring steel exhibited a multiphase microstructure composed of martensite, bainite and retained austenite (RA). As the austempering temperature increased, the proportion of martensite gradually decreased, while the proportion of bainite significantly increased, and the proportion of RA first increased and then slightly decreased. The carbon content and stability of RA gradually increased. The toughness and ductility of steel gradually increased, while the strength decreased gradually. At the austempering temperature of 240 °C for 90 min, due to the presence thin and long lath bundles of martensite and bainite, as well as the effective synergy between multiphase microstructure, the spring steel exhibited excellent comprehensive properties with an ultimate tensile strength of 2578 MPa, a total elongation of 11.2 %, an impact toughness of 11.8 J, and PSE of 28.6 GPa%. After the austempering treatment at 350 °C for 90 min, the highly stable RA in the spring steel exhibited a sustained TRIP effect during the tensile process. The RA gradually transformed into twinned martensite, enabling the spring steel to exhibit a long-lasting work hardening capacity and achieve excellent toughness and ductility, resulting in a total elongation of 24.1 %, an impact toughness of 29.2 J, and a PSE of 36.4 GPa%.

Abstract Background Numerous studies have indicated that cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, there are still many unknowns regarding the exact role of CAF subtypes in CRC. Methods The data for this study were obtained from bulk, single-cell, and spatial transcriptomic sequencing data. Bioinformatics analysis, in vitro experiments, and machine learning methods were employed to investigate the functional characteristics of CAF subtypes and construct prognostic models. Results Our study demonstrates that Biglycan (BGN) positive cancer-associated fibroblasts (BGN + Fib) serve as a driver in colorectal cancer (CRC). The proportion of BGN + Fib increases gradually with the progression of CRC, and high infiltration of BGN + Fib is associated with poor prognosis in terms of overall survival (OS) and recurrence-free survival (RFS) in CRC. Downregulation of BGN expression in cancer-associated fibroblasts (CAFs) significantly reduces migration and proliferation of CRC cells. Among 101 combinations of 10 machine learning algorithms, the StepCox[both] + plsRcox combination was utilized to develop a BGN + Fib derived risk signature (BGNFRS). BGNFRS was identified as an independent adverse prognostic factor for CRC OS and RFS, outperforming 92 previously published risk signatures. A Nomogram model constructed based on BGNFRS and clinical-pathological features proved to be a valuable tool for predicting CRC prognosis. Conclusion In summary, our study identified BGN + Fib as drivers of CRC, and the derived BGNFRS was effective in predicting the OS and RFS of CRC patients.

Abstract Background Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. Methods The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1’s role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. Results Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. Conclusions Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.

This review provides a comprehensive overview of recent advances in biodegradable materials for sustainable food packaging applications. Biodegradable polymers offer an alternative to conventional plastics by undergoing decomposition into water, carbon dioxide, and biomass. Synthetic biopolymers like PLA, PHAs, and bio-based polyesters as well as natural biopolymers such as polysaccharides and proteins have shown promise as substitutes for non-biodegradable packaging. These materials provide sustainability, waste reduction, and carbon neutrality benefits. However, inferior barrier properties, low heat resistance, poor mechanical strength, and high costs are limitations. Strategies like plasticization, blending, nanomaterial reinforcement, and multilayer composite structures have expanded biopolymer applicability for various foods. Biodegradation and life cycle assessment studies have demonstrated their environmental advantages over conventional plastics. Addressing remaining challenges in collection logistics, composting infrastructure, costs, and functional performance will be crucial for widespread commercial adoption. Recent advances make biopolymer packaging poised to make major contributions to sustainable development in the food industry.

The relationship between the intrinsic properties of seven different types of fly ash and the compressive strength of the resulting geopolymers was investigated. A comprehensive examination of the effect of chemical and mineralogical compositions, particle size distribution, on the compressive strength of the fly ash-based geopolymers were performed. Results revealed that particle size distribution had a more significant impact on reaction activity than amorphous phase content or average particle size alone. Therefore, a novel concept of 'reaction volume' based on the geopolymerization reaction mechanism was proposed, which reveals a high correlation between the reactivity of fly ash and the compressive strength of geopolymers, thereby enhancing the predictability of the process. The degree of reactivity, formulated through the integration of reaction volume and amorphous silica-aluminum content, was identified as a robust predictor of compressive strength, which can serve as a crucial tool for evaluating fly ash for the production of alkali-activated materials.

Acute kidney injury (AKI) is characterized by a rapid loss of renal metabolic function and a high mortality rate. Although significant progress has been made in developing targeted drugs for AKI treatment, issues such as inadequate antioxidant effects and poor renal enrichment efficiency remain. Nanomotors can enhance drug delivery efficiency in AKI treatments through self-propulsion in the microenvironment or via external stimuli. We reviewed recent progress in the targeted treatment of AKI with nanomotors, focusing on their contribution to targeted drug delivery at different stages and combined treatments. Current limitations and future development directions are also discussed.

Commented article: ZHANG, F. H. Contrast Between Chinese and Western Cultural Values and Its Effects on English Learning in China. Trans/Form/Ação: revista de filosofia da Unesp, v. 47, n. 4, “Eastern thought”, e0240062, 2024. Available at: https://revistas.marilia.unesp.br/index.php/transformacao/article/view/14621.

The Qilian orogenic belt (QOB) located in the northeast margin of the Tibetan Plateau is featured by remarkable crustal thrusting and shortening, providing a key natural example to understand the lithospheric deformation of the Tibetan Plateau. Two types of continental collision are observed in the QOB: lithosphere subduction beneath Southern Qilian and crust underthrusting of Alxa terrain along the North Border Thrust (NBT). Deep seismic reflection profiles reveal complex stress field evolution, including compressional deformation in the lower crust, extensional deformation in the upper crust, and detachment deformation in the middle crust. In this study, we use 2D numerical modeling to investigate the dynamics of these two different collision types and the evolution of Qilian uplift. Model results suggest three patterns of continental collision, i.e., crust underthrusting follows lithosphere subduction, lithosphere subduction and the failed underthrusting/subduction. The key factors that may influence model evolution, including crustal rheology, convergence direction and rate, are systematically investigated. Our model results are further compared to observations, suggesting that lower convergence rate and crust underthrusting along NBT likely control the uplift and crust stress stratification of the QOB.

This study employs two-temperature molecular dynamics simulations to investigate swift heavy ion irradiation of SiO2 substrate-supported two-dimensional material graphene. Material-dependent electronic and thermal properties are integrated into each region to model the energy transfer between the electronic and atomic subsystems of the studied materials. Simulations of interactions with Xe heavy ions are performed with ion kinetic energies ranging from 0.5 to 25 GeV with electronic stopping powers from ∼2.6 to 17.7 keV/nm. With the studied ion energy range, nanopores with a diameter of up to 5 nm can be formed in graphene due to the thermally driven sputtering effect, while amorphization occurs along the ion track in the SiO2 substrate. The coupling between the substrate and two-dimensional material significantly impacts the structural change due to heat transfer and atomic interactions among different layers of materials. The method applied in this work provides a valuable tool for modeling and understanding the structural modifications induced by ion irradiation in layered structures.

ObjectiveTo investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes.MethodsThis retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients’ CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs.ResultsA total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%–45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065).ConclusionCCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

Abstract The Central Asian Orogenic Belt (CAOB) was formed by the aggregation and collage of numerous Paleozoic subduction‐accretion assemblages and Precambrian microcontinental blocks. However, the tectonic nature of the southeastern CAOB remains controversial, which complicates the reconstruction of the Paleo‐Asian Ocean. To address this issue, a deep seismic reflection survey was initiated across the southeastern CAOB and reveals broad gentle sub‐horizontal reflectors in the middle‐lower crust and a relatively transparent zone in the upper crust. Combining with the Precambrian geological outcrops and other geophysical features, we support a microcontinental block, the Xilinhot Block, existed in the Paleo‐Asian domain. Thus, the Paleo‐Asian Ocean was separated into two branches that underwent north‐dipping and double‐dipping oceanic plate subduction, respectively, to form the Hegenshan‐Heihe and Solonker sutures. Multiple relics beneath Hegenshan‐Heihe Suture indicate that multiple sets of unidirectional oceanic subduction‐accretion and magmatism were important mechanisms of continental growth.

Abstract The Molucca Sea subduction zone is unique for its active divergent double‐subducted slab located in the north of the Java and Banda subduction zones. The spatial proximity of these subduction zones would cause a complex mantle flow field. To clarify the mantle dynamics, here we present P‐wave tilting‐axis anisotropic tomography obtained by inverting a large number of local and teleseismic travel‐time data recorded at 254 seismic stations in eastern Southeast Asia. Our results suggest that the mantle structure and dynamics of the western Molucca Sea subduction zone may be remotely controlled by the Java and Banda subduction zones. Mantle convection in the big mantle wedge west of the Molucca Sea subduction zone is possibly influenced by east‐west mantle flow associated with compression of the Indo‐Australian slab as well as north‐south mantle flow related to rollback of the Indo‐Australian slab. In contrast, the eastern Molucca Sea subduction zone is virtually unaffected by other subduction zones, probably due to the ongoing slab subduction there.

Osmoregulation is essential for aquatic organisms to balance their internal fluids and ions and adapt to environmental changes. The gills are a crucial organ for maintaining osmotic balance in fish by regulating the uptake and excretion of ions. Changes in the salinity of the aquatic environment can lead to alterations in the expression of genes within gill cells, which helps to maintain the internal salinity balance and allows the fish to adapt to different salinity levels. In this study, we used transcriptomic data of the gill from the euryhaline Takifugu obscurus and the stenohaline Takifugu rubripes, as well as their hybrid offspring (Tor1 and Tor2), to investigate how the gill contributes to osmoregulation in response to freshwater and seawater. Our study revealed 8 commonly differentially expressed genes among these four fish species. Analysis of the T. obscurus transcriptome data has demonstrated that SLC1a5, a member of the solute carrier (SLC) family, and Gper1, a G-protein coupled estrogen receptor 1-like, are enriched in many biological processes and might be important for its osmoregulation in freshwater. Furthermore, PDE8B, Lrrc9 and Cplx4 might be important osmoregulatory genes that are inherited by offspring in T. obscurus. Moreover, upon encountering changes in water salinity, T. rubripes and the hybrid offspring Tor1 reveal a marked concentration of differentially expressed genes in metabolic pathways within their gills, whereas T. obscurus and the hybrid offspring Tor2 show a more even distribution of DEGs across various signaling pathways. Finally, the Pearson correlation analysis revealed that the T. rubripes displayed a significant correlation with Tor1, while the T. obscurus was significantly related to Tor2. Overall, this study provides a theoretical foundation for understanding the salinity adaptation mechanisms in hybrid offspring of Takifugu, and holds significant implications for guiding the breeding of economically valuable Takifugu strains with improved traits.

Key Clinical Message Traumatic posterior atlantoaxial dislocation combined with Jefferson fracture and odontoid process fracture with vertebral artery injury is rare. The management of such injury raises controversial issues and is still open to debate. A 74‐year‐old Chinese male presented with sustained neck pain and stiffness after falling from height. The patient was neurologically intact. Preoperative radiographs demonstrated a Jefferson burst fracture with a posterior dislocation of the atlantoaxial joints and odontoid process Anderson and D'alonzo type II fracture. A computed tomography angiography (CTA) showed an occluded left vertebral artery. Coil embolization in the proximal portion of the occluded vertebral artery was performed to prevent further cerebral infarction due to distal embolization of the thrombus. Then a second stage occipito‐cervical fusion was performed to reconstruct cervical spine stability. A systematic screening of blunt trauma vertebral artery injuries through CTA is required when dealing with upper cervical fracture. For cases with vertebral artery occlusion secondary to cervical spine injury, endovascular treatment preceding cervical spine surgery is a feasible and a safe treatment.

Fugu (Takifugu rubripes) is a commercially important fish in aquaculture in China, Japan, and Korea. Male fugu are highly prized compared to females because the mature testes are regarded as a delicacy, thus all-male populations are preferred in aquaculture. However, the molecular mechanisms underlying sex differentiation in fugu remain largely unclear. Progestins, which are mediated by the progesterone receptor, can initiate spermatogenesis or ovarian differentiation in teleosts. To explore the effect of progestin blockage on fugu sex differentiation, the antiprogestin mifepristone (RU486) (500 μg/g of feed) was administrated to fugu larvae from 30 to 90 days after hatching (dah). Histological analysis revealed that RU486 treatment resulted in complete masculinization (100 %) of the XX fugu population at both 120 (RU486 withdrawal 30 days) and 150 (RU486 withdrawal 60 days) dah, and RU486-treated XX gonads developed testes-like structure. Gonadal transcriptomic analysis at 90 dah identified 3595 genes that were differentially expressed (DEGs) between the control and treated groups. Among them, the expression of steroid hormone biosynthesis-related genes (e.g., cyp11c1, cyp19a1a, and hsd17b1) and other key genes (e.g., gsdf, dmrt1, and foxl2) were altered in the gonads of RU486-treated groups. Most of the DEGs were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to sex differentiation, such as neuroactive ligand-receptor interaction, ovarian steroidogenesis, and steroid hormone biosynthesis pathways. The expression of cyp19a1a, foxl2, cyp11c1, gsdf, dmrt3, and dmrt1 at 50, 70, and 90 dah was further assessed. The expression levels of gsdf, dmrt1, and cyp11c1 were increased, and the expression levels of cyp19a1a and foxl2 were decreased in the gonads of XX larvae in RU486 treated groups. These results demonstrated for the first time that RU486 induced masculinization in XX fugu and provided a theoretical basis for further studies of the regulatory role of progestins in sex differentiation in teleosts.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation.Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method.Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed.Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

BackgroundPolycystic ovary syndrome (PCOS) is the most common reproductive–endocrine disorder with wide-ranging metabolic implications, including obesity. RNA editing, a post-transcriptional modification, can fine-tune protein function and introduce heterogeneity. However, the role of RNA editing and its impact on adipose tissue function in PCOS remain poorly understood.MethodsThis study aimed to comprehensively analyze RNA-editing events in abdominal and subcutaneous adipose tissue of PCOS patients and healthy controls using high-throughput whole-genome sequencing (WGS) and RNA sequencing.ResultsOur results revealed that PCOS patients exhibited more RNA-editing sites, with adenosine-to-inosine (A-to-I) editing being prevalent. The expression of ADAR genes, responsible for A-to-I editing, was also higher in PCOS. Aberrant RNA-editing sites in PCOS adipose tissue was enriched in immune responses, and interleukin-12 biosynthetic process. Tumor necrosis factor (TNF) signaling, nuclear factor kappa B (NF-κB) signaling, Notch signaling, terminal uridylyl transferase 4 (TUT4), hook microtubule tethering protein 3 (HOOK3), and forkhead box O1 (FOXO1) were identified to be of significant differences. Differentially expressed genes (DEGs) in PCOS adipose tissue were enriched in immune responses compared with controls, and the DEGs between subcutaneous and abdominal adipose tissue were also enriched in immune responses suggesting the important role of subcutaneous adipose tissue. Furthermore, we identified the correlations between RNA editing levels and RNA expression levels of specific genes, such as ataxia–telangiectasia mutated (ATM) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) in inflammation pathways and ATM, TUT4, and YTH N6-methyladenosine RNA-binding protein C2 (YTHDC2) in oocyte development pathway.ConclusionsThese findings suggest that RNA-editing dysregulation in PCOS adipose tissue may contribute to inflammatory dysregulations. Understanding the interplay between RNA editing and adipose tissue function may unveil potential therapeutic targets for PCOS management. However, further research and validation are required to fully elucidate the molecular mechanisms underlying these associations.

Suaeda glauca Bunge produces dimorphic seeds on the same plant, with brown seeds displaying non-dormant characteristics and black seeds exhibiting intermediate physiological dormancy traits. Previous studies have shown that black seeds have a very low germination rate under natural conditions, but exogenous GA3 effectively enhanced the germination rate of black seeds. However, the physiological and molecular mechanisms underlying the effects of GA3 on S. glauca black seeds are still unclear. In this study, transcriptomic profiles of seeds at different germination stages with and without GA3 treatment were analyzed and compared, and the TTF, H2O2, O2–, starch, and soluble sugar contents of the corresponding seed samples were determined. The results indicated that exogenous GA3 treatment significantly increased seed vigor, H2O2, and O2– contents but decreased starch and soluble sugar contents of S. glauca black seeds during seed dormancy release. RNA-seq results showed that a total of 1136 DEGs were identified in three comparison groups and were involved mainly in plant hormone signal transduction, diterpenoid biosynthesis, flavonoid biosynthesis, phenylpropanoid biosynthesis, and carbohydrate metabolism pathway. Among them, the DEGs related to diterpenoid biosynthesis (SgGA3ox1, SgKAO and SgGA2ox8) and ABA signal transduction (SgPP2Cs) could play important roles during seed dormancy release. Most genes involved in phenylpropanoid biosynthesis were activated under GA3 treatment conditions, especially many SgPER genes encoding peroxidase. In addition, exogenous GA3 treatment also significantly enhanced the expression of genes involved in flavonoid synthesis, which might be beneficial to seed dormancy release. In accordance with the decline in starch and soluble sugar contents, 15 genes involved in carbohydrate metabolism were significantly up-regulated during GA3-induced dormancy release, such as SgBAM, SgHXK2, and SgAGLU, etc. In a word, exogenous GA3 effectively increased the germination rate and seed vigor of S. glauca black seeds by mediating the metabolic process or signal transduction of plant hormones, phenylpropanoid and flavonoid biosynthesis, and carbohydrate metabolism processes. Our results provide novel insights into the transcriptional regulation mechanism of exogenous GA3 on the dormancy release of S. glauca black seeds. The candidate genes identified in this study may be further studied and used to enrich our knowledge of seed dormancy and germination.

In recent years, pedestrian tracking algorithms have witnessed extensive utilization in various domains. Particularly noteworthy is the attention garnered by hospital pedestrian tracking due to its potential to enhance operational efficiency and patient’s safety. The continuously stable and accurate patients’ position information can help hospitals to guarantee that patients remain within designated areas and get timely assistance when necessary. In this work, in order to improve the robustness of the data fusion filter for the pedestrian tracking, one robust error state FIR filter (ESFIR) will been proposed. To the data fusion model, the quaternion-based data fusion models for the accelerometer will be firstly derived, which can improve the accuracy of sensor data for the Zero velocity UPdaTe (ZUPT) by using the quaternion-based state vector and the accelerometer value as the measurement. Then, two filters are used to reduce the error accumulation in inertial navigation system (INS): with the data of accelerometer and gyroscope, the ESFIR filter is employed to provide the error estimation of the accelerometer, which is used to correct the accelerometer’s output directly, then, the finite impulse response (FIR) filter will be used in the Zero velocity UPdaTe (ZUPT) method. With the Gyroscope’s output and the ESFIR corrected accelerometer data, the human position can be computed. Finally, four real tests will be done to verify the performance of the proposed method. The actual test results show that the accuracy of the position information derived from the solution using this method is improved by 8.43% on average compared with the conventional Kalman-based method when the setting is friendly to KF. When the setting is bad for KF, the KF-based method has divergence, and the proposed method can still provide stable solution, it can improve the localization accuracy by about 11.81% when compared with the INS+ZUPT method, thus providing better robustness.

Purposes Aiming at the problem that the randomized neighbor list method of directly disturbing the neighbor list in the existing local differential privacy social network graph generation algorithm will lead to excessive noise and imbalanced privacy protection, a new social network graph generation algorithm satisfying personalized local differential privacy is proposed. Methods First, the Louvain algorithm is used to partition the original social network graph and preserve community information; Second, for the divided community, a new privacy budget parameter is allocated to each node on the basis of the average weight ratio within the community; Then each node perturbs its neighbor list separately, meanwhile by using the Randomized Adjacency Bit Vector method to reduce communication consumption; Finally, merge the neighbor lists are merged to form a generated graph. Findings The experimental results on real datasets show that this algorithm ensures a balance between data privacy and availability when publishing synthetic graph data, while retaining more community structure information.

Abstract Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3′UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

BackgroundVolatile organic compounds (VOCs) in exhaled breath are closely associated with respiratory diseases and are linked to various metabolic reactions in the human body. A quantitative analytical method can provide technical support for studying VOCs related to various diseases. ObjectiveTo establish a thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) method for the determination of 27 VOCs in exhaled breath. MethodsVOCs in exhaled breath were collected using a Bio-VOC sampler and enriched with Tenax TA thermal desorption tubes before TD-GC-MS analysis. Standards were collected using thermal desorption tubes and optimized for thermal desorption conditions as well as chromatographic and mass spectrometric conditions: The separation of the 27 VOCs was achieved by an optimized temperature program, the improvement of sensitivity by optimizing quantitative ions, and the increase of VOCs desorption efficiency by optimizing thermal desorption time and temperature. Limit of detection, limit of quantification, accuracy, precision, and stability of the proposed method were investigated by spiking with a blank gas bag, and exhaled breath samples from 20 healthy individuals were collected for an application study of the proposed method. ResultsThe thermal desorption temperature was 280 ℃, and desorption time was 6 min. A VF-624ms chromatographic column was selected for the separation of target substances. The initial temperature of heating program was 35 ℃, maintained for 1 min, and then increased to 100 ℃ at a heating rate of 3 ℃·min−1 for 1 min, followed by increasing to 210 ℃ at a heating rate of 28 ℃·min−1 for 5 min. A quantitative analysis was conducted with a single ion monitoring (SIM) mode. Under these conditions, the 27 VOCs showed good linear relationships in their respective concentration ranges and the correlation coefficients were higher than 0.9990. The limits of detection of the method were in the range of 0.01-0.13 nmol·mol−1, the limits of quantification were in the range of 0.02-0.44 nmol·mol−1, and the spiked recoveries were in the range of 80.1%-120.5%, with intra-batch and inter-batch precision ≤ 18.8% and 17.9% respectively. All substances can be stored at room temperature (23-28 °C) for 7 d and at 4 °C for 14 d. The proposed method was applied to exhaled breath samples from 20 subjects with detection rates≥ 80% (except for trans-2-pentene and decane) and a concentration range of 0.00-465.50 nmol·mol−1. ConclusionThe established TD-GC-MS method for quantification of VOCs in exhaled breath is characterized by high sensitivity and good accuracy, and is suitable for quantitative determination of VOCs in exhaled breath, which can provide technical support for the study of exhaled breath VOCs.