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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.

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.

Abstract Asparagus, a vital economic contributor, is a well‐liked vegetable grown around the globe, and some secondary metabolites in its spear are beneficial to human health. Asparagus spears possess a significant quantity of nutrients and phytochemicals; however, the difference in these chemical compositions among various varieties has not been sufficiently studied. This work aimed to detect the chemical compositions of 30 varieties of asparagus and to assess them by principal component analysis (PCA). The results showed that the contents of these chemical compositions varied in varieties. Selenium (Se, 1.12–2.9 μg/100 g dry‐weight [DW]) was abundant in asparagus, with an average dry matter content of 8.25%. Free amino acids (5.60–9.98 g/100 g DW) and polyphenols (6.34–8.67 mg/g DW) were both present in high amounts, along with flavonoids (4.218–8.22 mg/g DW) and protodioscin (0.44–1.96 mg/g DW). Correlation analysis, PCA, and hierarchical cluster analysis were used to conduct a comprehensive evaluation of asparagus. Atlas, Appolo, Jinggang 111, Jingke 2, and WS‐1 were the top five varieties with comprehensive scores. This study provided valuable data for the breeding, quality improvement, processing, and utilization of asparagus varieties in the future.

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.

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.

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.

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.

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.

During the past half-century, although numerous interventions for obesity have arisen, the condition’s prevalence has relentlessly escalated annually. Obesity represents a substantial public health challenge, especially due to its robust correlation with co-morbidities, such as colorectal cancer (CRC), which often thrives in an inflammatory tumor milieu. Of note, individuals with obesity commonly present with calcium and vitamin D insufficiencies. Transient receptor potential canonical (TRPC) channels, a subclass within the broader TRP family, function as critical calcium transporters in calcium-mediated signaling pathways. However, the exact role of TRPC channels in both obesity and CRC pathogenesis remains poorly understood. This study set out to elucidate the part played by TRPC channels in obesity and CRC development using a mouse model lacking all seven TRPC proteins (TRPC HeptaKO mice). Relative to wild-type counterparts, TRPC HeptaKO mice manifested severe obesity, evidenced by significantly heightened body weights, augmented weights of epididymal white adipose tissue (eWAT) and inguinal white adipose tissue (iWAT), increased hepatic lipid deposition, and raised serum levels of total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C). Moreover, TRPC deficiency was accompanied by an decrease in thermogenic molecules like PGC1-α and UCP1, alongside a upsurge in inflammatory factors within adipose tissue. Mechanistically, it was revealed that pro-inflammatory factors originating from inflammatory macrophages in adipose tissue triggered lipid accumulation and exacerbated obesity-related phenotypes. Intriguingly, considering the well-established connection between obesity and disrupted gut microbiota balance, substantial changes in the gut microbiota composition were detected in TRPC HeptaKO mice, contributing to CRC development. This study provides valuable insights into the role and underlying mechanisms of TRPC deficiency in obesity and its related complication, CRC. Our findings offer a theoretical foundation for the prevention of adverse effects associated with TRPC inhibitors, potentially leading to new therapeutic strategies for obesity and CRC prevention.

Abstract Geochemical reactions are crucial for in situ CO2 mineralization underground associated with CO2‐enhanced oil recovery (CO2‐EOR) in a hydrocarbon reservoir. However, the presence of formation water and adsorbed oil on rocks generates physical barriers to CO2's access to mineral surfaces, which may yield impedance to CO2 mineral trapping that has yet to be accounted for. In this study, we mimic the dynamic oil detachment process using molecular dynamic (MD) simulation and analyze the influence of an adsorbed oil film on supercritical CO2 (scCO2) diffusion toward the mineral surface in the presence and absence of a water phase. Our results demonstrated a negative impact of water on oil film detachment by scCO2, which may weaken mineral reactions and is unfavorable for mineralized CO2 storage underground.

BackgroundAnorexia nervosa (AN) and bulimia nervosa (BN) poses a significant challenge to global public health. Despite extensive research, conclusive evidence regarding the association between gut microbes and the risk of AN and BN remains elusive. Mendelian randomization (MR) methods offer a promising avenue for elucidating potential causal relationships.Materials and methodsGenome-wide association studies (GWAS) datasets of AN and BN were retrieved from the OpenGWAS database for analysis. Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa from the MiBioGen consortium were identified as instrumental variables. MR analysis was conducted utilizing R software, with outlier exclusion performed using the MR-PRESSO method. Causal effect estimation was undertaken employing four methods, including Inverse variance weighted. Sensitivity analysis, heterogeneity analysis, horizontal multivariate analysis, and assessment of causal directionality were carried out to assess the robustness of the findings.ResultsA total of 196 bacterial taxa spanning six taxonomic levels were subjected to analysis. Nine taxa demonstrating potential causal relationships with AN were identified. Among these, five taxa, including Peptostreptococcaceae, were implicated as exerting a causal effect on AN risk, while four taxa, including Gammaproteobacteria, were associated with a reduced risk of AN. Similarly, nine taxa exhibiting potential causal relationships with BN were identified. Of these, six taxa, including Clostridiales, were identified as risk factors for increased BN risk, while three taxa, including Oxalobacteraceae, were deemed protective factors. Lachnospiraceae emerged as a common influence on both AN and BN, albeit with opposing effects. No evidence of heterogeneity or horizontal pleiotropy was detected for significant estimates.ConclusionThrough MR analysis, we revealed the potential causal role of 18 intestinal bacterial taxa in AN and BN, including Lachnospiraceae. It provides new insights into the mechanistic basis and intervention targets of gut microbiota-mediated AN and BN.

Summary: Embryos, originating from fertilized eggs, undergo continuous cell division and differentiation, accompanied by dramatic changes in transcription, translation, and metabolism. Chromatin regulators, including transcription factors (TFs), play indispensable roles in regulating these processes. Recently, the trophoblast regulator TFAP2C was identified as crucial in initiating early cell fate decisions. However, Tfap2c transcripts persist in both the inner cell mass and trophectoderm of blastocysts, prompting inquiry into Tfap2c’s function in post-lineage establishment. In this study, we delineate the dynamics of TFAP2C during the mouse peri-implantation stage and elucidate its collaboration with the key lineage regulators CDX2 and NANOG. Importantly, we propose that de novo formation of H3K9me3 in the extraembryonic ectoderm during implantation antagonizes TFAP2C binding to crucial developmental genes, thereby maintaining its lineage identity. Together, these results highlight the plasticity of the chromatin environment in designating the genomic binding of highly adaptable lineage-specific TFs and regulating embryonic cell fates.

Summary: Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca2+ on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca2+ (Cav) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca2+ oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca2+ with cyclopiazonic acid or blocking ER Ca2+-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca2+ mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca2+ influx through P/Q-type Cav channels. ω-Agatoxin IVA blocked α-cell ER Ca2+ release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca2+ mobilization, a mechanism that can be independent of α-cell electrical activity.

The karst that is dominated by medium-weathered limestone and caves with various spatial features is widely distributed in the northern Fujian Province. This paper discusses the load-bearing behaviors of post-grouting tubular piles in karst region of north Fujian Province with reference to the prestressed tubular piles adopted in the residential buildings of Haixi Comprehensive Trade City Phase II Project in Sanming City. The load-settlement curve, pile side friction resistance, and pile end resistance of tubular piles are analyzed by finite element numerical simulations and field static load tests. The load-bearing behaviors of prestressed tubular piles under karst geological conditions with two different spatial features are comparatively investigated, and the effectiveness of tubular pile reinforcement is verified by field settlement observation. The results reveal that the finite element numerical model can effectively simulate the tubular pile-soil interaction. The use of pile end post-grouting of prestressed tubular piles in the karst region can significantly increase their load-bearing capacities. The top settlements of grouted tubular piles under the maximum test load can be reduced by 16.8%–22.3% compared with these of ungrouted test piles, and the theoretical simulated ultimate load-bearing capacity can be increased by 27.3%. The adoption of pile end post-grouting technique can reduce the pile end displacement of tubular piles and improve the proportion of pile end resistance. Plastic-hard plastic breccia silty clay can be used as a bearing stratum for post-grouting to achieve excellent grouting performance. The bead-shaped karst caves are more unfavorable to the exertion of load-bearing capacity of the tubular piles than the karst caves filled with plastic-hard plastic breccia silty clay to which the piles have direct access. The field monitored average settlements of the 19# and 17# buildings under karst geological conditions with two different spatial features are −12.88 mm and −8.98 mm, respectively, both of which do not exceed the warning value, indicating that it is feasible for the project to adopt the pile end post-grouting technique of the tubular piles. The achievements of this study help to further reveal the load-bearing mechanism of this type of pile, which can provide a basis for its engineering design and construction optimization.

Abstract Background Mental health literacy is considered an important factor in promoting professional psychological help-seeking attitudes. However, it is important to clarify the emotional and behavioral factors that underlie this association. Drawing from the ABC model of attitudes and the Health Disclosure Decision-Making Model, this study aimed to examine the mediating role of psychological help-seeking stigma and distress disclosure in the relationship between mental health literacy and professional psychological help-seeking attitudes. Methods We collected data from 827 participants in seven regions of China (597 female; M age = 26.019, SD = 5.592 years old) using self-report measures, including the Mental Health Literacy Scale, Questionnaire of Stigma for Seeking Professional Psychological Help, Distress Disclosure Index, and Attitudes Toward Seeking Professional Psychological Help-Short Form. A chain mediation model was built to examine the relationships among mental health literacy, psychological help-seeking stigma, distress disclosure, and professional psychological help-seeking attitudes. Results The results of the analyses showed a positive association between mental health literacy and professional psychological help-seeking attitudes, with psychological help-seeking stigma and distress disclosure playing mediating roles in this relationship. Furthermore, even after controlling for participants’ age, gender, and education, the chain mediation effect of psychological help-seeking stigma and distress disclosure on the relationship between mental health literacy and professional psychological help-seeking attitudes was observed among the Chinese population. Conclusions These findings underscore the significance of mental health literacy in shaping professional psychological help-seeking attitudes, while emphasizing the need to account for psychological help-seeking stigma and distress disclosure when examining this association. Additionally, the model proposed in this study provides a valuable framework for promoting the utilization of professional mental health services.

Abstract Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An adjunctive therapy in COPD includes the simultaneous administration of astragalus injection and ambroxol hydrochloride. Despite its widespread use, the effectiveness of this combined approach in COPD treatment has not been systematically evaluated. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of combining astragalus injection with ambroxol hydrochloride as an adjuvant treatment for COPD. Six electronic databases were used to search for relevant randomized controlled trials, and data analysis was conducted using Review Manager 5.4. A total of 14 randomized controlled trials were included, involving 1070 patients who met the criteria. The results of the meta-analysis indicated that the combination of astragalus injection with ambroxol hydrochloride as an adjuvant treatment can improve various clinical parameters in patients with COPD compared to conventional treatment alone. These parameters include the clinical effective rate (OR = 5.44, 95% CI 3.51–8.43, I2 = 0%), partial pressure of oxygen in artery (MD = 1.12, 95% CI 0.87–1.36, I2 = 5%), partial pressure of carbon dioxide in artery (MD = − 1.43, 95% CI − 1.65 to − 1.21, I2 = 0%), forced expiratory volume in one second (MD = 0.30, 95% CI 0.18–0.42, I2 = 0%), percentage of forced expiratory volume in one second (MD = 16.18, 95% CI 12.60–19.76, I2 = 82%), forced vital capacity (MD = 0.33, 95% CI 0.21–0.45, I2 = 36%), hemoglobin (MD = − 16.17, 95% CI − 20.84 to − 11.51, I2 = 29%), and the ratio of forced expiratory volume in one second to forced vital capacity (MD = 2.51, 95% CI − 0.05 to 5.06, I2 = 0%). The combination of astragalus injection and ambroxol hydrochloride could be a selection of COPD patients as an adjuvant treatment. However, further validation is required to evaluate the effectiveness of combining astragalus injection and ambroxol hydrochloride as an adjunctive treatment for patients with COPD.

Abstract Development is a fundamental pursuit of human society. When it comes to national governance, there are issues of imbalanced and insufficient development that must be addressed. Since 1949, when the People’s Republic of China was founded, the Chinese government has adopted a series of ethnic policies to resolve these development issues across ethnic minority areas. Since the late 1970s, Chinese scholars and the government have paid particular attention to the development issues of ethnic groups with smaller populations. This paper examines the relevant literature on this topic and divides China’s policies on this issue into three stages: (1) initial exploration, (2) targeted assistance, and (3) specialized planning. It discusses the Chinese government’s policy process and its experience empowering ethnic groups with smaller populations. The paper argues that the Chinese government’s support for ethnic groups with smaller populations is guided by valid ethnic theories and a comprehensive policy system. In the implementation of policies, the government recognizes “development” as the primary objective. It then formulates, implements, and evaluates policies based on the characteristics of the different ethnic groups with smaller populations. This approach effectively addressed the problems faced by these ethnic groups during different stages of their development and achieved the intended policy goals. Therefore, these policies are practical and sustainable. They are a valuable asset, and studying them could be beneficial to any unified multi-ethnic country that wants to tackle the development issues of their ethnic minorities.

Abstract Background Blinding drugs through simulation techniques is an important means to control the subjective bias of investigators and subjects. However, clinical trials face significant challenges in the placebo production of drugs, and many trials cannot be double-blinded. Objective This study was conducted to ascertain the consistency between non-blind and blind evaluation results in clinical trials and to pioneer strategies to control information bias, particularly in trials where double-blinding is not feasible. Methods In this investigation, a randomized controlled trial (RCT) studying diabetic foot infections (DFIs) was utilized as a representative case. In this trial, the grading of DFIs, as per guidelines by the Infectious Disease Society of America (IDSA) and International Working Group on Diabetic Foot (IWGDF), was used as the primary efficacy indicator. A sample of sixteen patients was randomly chosen from the RCT, and DFI grading was assessed jointly by both non-blinded investigators and blinded center-reading investigators. A consistency test was then deployed to compare the evaluation results, forming the basis for our proposed strategies for effective blinded evaluation. In addition, other perspectives were collected at the end of this study, including with those involved in designing and conducting the recent blinded evaluation trial. Results Five subjects were excluded due to the quality of photos or the lack of post-treatment visits. The post-treatment IDSA/IWGDF grading results were compared in 11 subjects (experimental group=6, control group=5), and the consistency test showed inconsistent results between the non-blinded and center reading blinded evaluations (Kappa=0.248, p=0.384). In the experimental group, three cases were judged as grade 1 in the non-blinded evaluation and grade 2 in the central reading blinded evaluation; in the control group, three cases were judged as grade 2 in the non-blinded evaluation and grade 1 in the central reading blinded evaluation. The sum of these two cases in 22 post-treatment determinations was 27% (6/22). Furthermore, researchers propose several strategies for implementing blinded evaluations in clinical trials after this trial, which encompass aspects such as staff allocation, training, participant management, trial drug administration, efficacy indicator collection, and safety event management. Conclusions The study highlighted that evaluations from non-blinded site investigators may potentially exaggerate the efficacy of the experimental group and that deep wounds can present challenges for observation via center-reading photos. These findings underline the vital necessity for objective assessment in open clinical trials, especially those where wound observation serves as the primary efficacy indicator. The study suggests the adoption of independent blinded investigators at each site, complemented by a comprehensive set of standard operating procedures for blinding evaluation. These measures could serve as an effective counterbalance to subjective bias, thereby augmenting the credibility and consistency of results in open clinical trials. The implications of these findings and recommendations could be of great significance for the design and execution of future open clinical trials, potentially bolstering the quality of clinical research in this area. Trial registration ChiCTR2000041443. Registered on December 2020

Maintaining the confidentiality and integrity of the messages during a transmission is one of the most important aims of encrypted communication systems. Many achievements were made using biomolecules to improve the quality of the messages in communication. At the same time, it is still a challenge to construct cooperative communications based on the interactions between biomolecules to achieve the confidentiality and integrity of the transmitted messages. DNA-based encrypted communications have been developed, and in particular, DNA-origami-based message encryption can combine steganography and pattern encryption and exhibits extremely high confidentiality. Nevertheless, limited by biological characteristics, encrypted messages based on DNA require a strict storage environment in the process of transmission. The integrity of the message encoded in the DNA may be damaged when the DNA is in an unfriendly and hard environment. Therefore, it is particularly significant to improve the stability of DNA when it is exposed to a harsh environment during transmission. Here, we encoded the information into the DNA strands that were condensed for encryption to form a nanosphere covered with a shell of SiO2, which brings high-density messages and exhibits higher stability than separated DNA. The solid shell of SiO2 could prevent DNA from contacting the harsh environment, thereby protecting the DNA structure and maintaining the integrity of the information. At the same time, DNA nanospheres can achieve high throughput input and higher storage density per unit volume, which contribute to confusing the message strand (M-strand) with the interference strand in the stored information. Condensing DNA into the nanosphere that is used for DNA origami cryptography has the potential to be used in harsh conditions with higher confidentiality and integrity for the transmitted messages.

Abstract Background Diabetic foot ulcers often affect tendon tissue. Consequently, the infection may spread proximally along the tendon, leading to amputation or even the death of patients. Exposed, degenerated, and necrotic tendons are key factors affecting the healing of diabetic foot ulcers. The effective treatment of the tendon involvement may positively affect the prognosis. In clinical practice, treatment with Shengji ointment and bromelain induces islands of granulation tissue on the denatured tendon surface, which gradually grows and merges. Ideally, the exposed tendon is covered entirely by granulation tissue. This trial aims to assess the effect of a combined treatment regime of Shengji ointment, which has been shown to regenerate muscle tissue and pineapple protease in preventing the loss of function and amputation caused by tendon necrosis. This trial will provide high-quality evidence for the effectiveness of this combination in healing diabetic ulcers with tendon necrosis. Methods The sample size will be 180 patients who will be randomly assigned 1:1 to a treatment group (90 patients) using Shengji ointment combined with bromelain and a control group (90 patients) using hydrocolloid dressing. Both groups will continue their conventional treatments, such as blood glucose and blood pressure medication, lipid regulation, antiplatelets, and others. The primary outcome will be the wound coverage with granulation tissue. Secondary outcomes will be the wound healing rate, amputation extent (where needed), time to granulation, and the Maryland Foot Score. Other efficacy outcomes will be the time to debridement of necrotic tendon tissue and granulation tissue score. Discussion This study will treat patients with diabetic foot ulcers with exposed, degenerated, and necrotic tendons with Shengji ointment and bromelain. The trial aims to promote regeneration and healing, to preserve the limb and its function, and to develop a comprehensive and effective protocol that can be applied to promote the healing of exposed tendons in diabetic foot wounds. Trial registration ChiCTR2000039327 ; date of registration: 2020-10-23.

With the development of electronic power technology, distributed clean energy harvesting is widely concerned, in the process of distributed energy harvesting, the process of monitoring energy harvesting equipment does not need to transmit a large amount of data to the host device, a small amount of status information can meet the purpose of monitoring, so in the wireless sensor network energy consumption is an important issue to be considered. It is very energy efficient, can transmit wireless data over long distances, and supports mesh networking. In the process of distributed energy harvesting, the wireless sensor network composed of LoRa can effectively monitor the environmental information and wireless energy harvesting system, and the battery requirement is very low, and the data can be distributed with very little power consumption, which can be used in harsh environment and remote mountainous areas. In this paper, the composition of the distributed energy harvesting system is discussed first, then the energy situation of LoRa in low-power wireless energy transmission is analyzed, and finally the wireless low-power sensor network is tested.

Accurately estimating rice yield is essential for ensuring global food security, enhancing agricultural productivity, and promoting agricultural economic growth. This study constructed a dataset of rice panicles at different growth stages and combined it with an attention mechanism and the YOLOv8 network to propose the YOLOv8s+LSKA+HorNet rice panicle detection and counting model, based on a drone remote sensing platform. Using the panicle count data collected by this model, along with the thousand-grain weight, number of grains per panicle, and actual yield data from a rice nitrogen gradient experimental field, various machine learning models were trained to ultimately propose a field-level rapid rice yield estimation model, RFYOLO. The experimental results show that the rice panicle detection and counting model can achieve an average precision (AP) of 98.0% and a detection speed of 20.3 milliseconds. The final yield estimation model achieved a prediction R2 value of 0.84. The detection and counting model significantly reduced missed and duplicate detections of rice panicles. Additionally, this study not only enhanced the model’s generalization ability and practicality through algorithmic innovation but also verified the impact of yield data range on the stability of the estimation model through the rice nitrogen gradient experiment. This is significant for early rice yield estimation and helping agricultural producers make more informed planting decisions.

Abstract The 180° curvature of the Banda arc at the eastern end of the Java‐Banda subduction zone reflects complicated geodynamic processes. A detailed investigation of its anisotropic structure would reveal its subduction dynamics, further resolving the controversial issue on how the highly arcuate Banda arc formed. We apply tilting‐axis anisotropic tomography to obtain a high‐resolution 3‐D anisotropic model beneath the Java‐Banda region. Our results show significant differences between Java and Banda in the pattern of anisotropy in both the subducting slab and its surrounding mantle, which reflect two distinctly different deformation modes in the two domains. Our results support the single‐slab subduction model for the Banda region. In addition, trench‐normal and upright fast‐velocity‐planes appear in the deep upper mantle, which may indicate material migrations in the big mantle wedge. Fast‐velocity‐planes in the shallow mantle exhibit a toroidal distribution, reflecting past counter‐clockwise rotation and asthenospheric material extrusion.

Abstract Targeting ferroptosis has attracted exponential attention to eradicate cancer cells with high iron‐dependent growth. Increasing the level of intracellular labile iron pool via small molecules and iron‐containing nanomaterials is an effective approach to induce ferroptosis but often faces insufficient efficacy due to the fast drug metabolism and toxicity issues on normal tissues. Therefore, developing a long‐acting and selective approach to regulate ferroptosis is highly demanded in cancer treatment. Herein, a lysosome‐targeted magnetic nanotorquer (T7‐MNT) is proposed as the mechanical tool to dynamically induce the endogenous Fe2+ pool outbreak for ferroptosis of breast cancer. T7‐MNTs target lysosomes via the transferrin receptor‐mediated endocytosis in breast cancer cells. Under the programmed rotating magnetic field, T7‐MNTs generate torques to trigger endogenous Fe2+ release by disrupting the lysosomal membrane. This magneto‐mechanical manipulation can induce oxidative damage and antioxidant defense imbalance to boost frequency‐ and time‐dependent lipid peroxidization. Importantly, in vivo studies show that T7‐MNTs can efficiently trigger ferroptosis under the magnetic field and play as a long‐acting physical inducer to boost ferrotherapy efficacy in combination with RSL3. It is anticipated that this dynamic targeted strategy can be coupled with current ferroptosis inducers to achieve enhanced efficacy and inspire the design of mechanical‐based ferroptosis inducers for cancer treatment.

Background Educational inequalities in suicide have become increasingly prominent over the past decade. Elucidating modifiable risk factors that serve as intermediaries in the impact of low educational attainment on suicide has the potential to reduce health disparities.Aims To examine the risk factors that mediate the relationship between educational attainment and suicide attempts and quantify their contributions to the mediation effect.Methods We conducted a two-sample Mendelian randomisation (MR) analysis to estimate the causal effect of educational attainment on suicide attempts, utilising genome-wide association study summary statistics from the Integrative Psychiatric Research (iPSYCH; 6024 cases and 44 240 controls) and FinnGen (8978 cases and 368 299 controls). We systematically evaluated 42 putative mediators within the causal pathway connecting reduced educational attainment to suicide attempts and employed two-step and multivariable MR to quantify the proportion of the mediated effect.Results In the combined analysis of iPSYCH and FinnGen, each standard deviation (SD) decrease in genetically predicted educational attainment (equating to 3.4 years of education) was associated with a 105% higher risk of suicide attempts (odds ratio (OR): 2.05; 95% confidence interval (CI): 1.81 to 2.31). Of the 42 risk factors analysed, the two-step MR identified five factors that mediated the association between educational attainment and suicide attempts. The respective proportions of mediation were 47% (95% CI: 29% to 66%) for smoking behaviour, 36% (95% CI: 0% to 84%) for chronic pain, 49% (95% CI: 36% to 61%) for depression, 35% (95% CI: 12% to 59%) for anxiety and 26% (95% CI: 18% to 34%) for insomnia. Multivariable MR implicated these five mediators collectively, accounting for 68% (95% CI: 40% to 96%) of the total effect.Conclusions This study identified smoking, chronic pain and mental disorders as primary intervention targets for attenuating suicide risk attributable to lower educational levels in the European population.