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Abstract Background Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM. Methods T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB. Results ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM. Conclusions ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy.

Abstract Background The most widely used anti-malarial drug artemisinin (ART) is metabolized extensively, but the therapeutic capacity of its major metabolite remains unknown. Whether the major metabolite of ART (ART-M) contributes to its antiplasmodial potency was investigated in this study. Methods The metabolite identification and enzyme phenotyping of ART were performed using human liver microsomes (HLMs). The stereostructure of the major metabolite ART-M was elucidated by spectroscopic and X-ray crystallographic analysis. The anti-malarial activity of ART-M against two reference Plasmodium strains (Pf3D7 and PfDd2) was evaluated. The pharmacokinetic profiles of ART and its metabolite ART-M were investigated in healthy Chinese subjects after a recommended two-day oral dose of ART plus piperaquine. Pharmacodynamic parameters based on minimum inhibitory concentration (MIC50) and free plasma concentration were employed to evaluate the therapeutic potency of ART-M, including fAUC0-t/MIC50, fCmax/MIC50 and T > MIC50. Results A major metabolite 10β-hydroxyartemisinin (ART-M) was found for ART in human, and CYP3A4/3A5 was the major enzymes responsible for ART 10β-hydroxylation. Compared with ART (MIC50, 10.1 nM against Pf3D7), weaker antiplasmodial activity was found for ART-M (MIC50, 61.4 nM against Pf3D7). However, a 3.5-fold higher maximal free plasma concentration was achieved for ART-M (fCmax, 180.0 nM vs. 51.8 nM for ART). ART-M displayed comparable antiplasmodial potency to ART, in terms of fAUC0-t/MIC50 (12.5 h), fCmax/MIC50 (2.8) and T > MIC50 (5 h). Conclusions The major metabolite 10β-hydroxyartemisinin contributes to the antiplasmodial efficacy of ART, which should be considered when evaluation of ART dosing regimens and/or clinical outcomes.

Abstract Background Chinese jujube (Ziziphus jujuba Mill.), also called Chinese date, is one of the oldest and widely cultivated fruit trees with great economic values, which, at least, can be attributed to the melliferous flower with highly developed nectary that can secret huge amount of nectar in a rather tiny floral size. However, the morphological nature, metabolic products, developmental process, as well as molecular and regulatory mechanisms of jujube nectary remain largely unknown. Results Here, we selected Z. jujuba ‘Dongzao’ as a system to address these questions. We uncovered that the jujube nectary is an annular or donut-shaped secretory protrusion that surrounds the base of the carpels, along with emerald and glistening hues, which can produce a bulk honey with many metabolic compounds (e.g. saccharides and flavonoids) that has a high nutritional value and benefit for human health. The development of jujube nectary is a dynamic process of earlier cell division followed by later cell expansion. We also identified putative genes associated with the nectary development and found that the CRABS CLAW (CRC) ortholog (ZjCRC) is the key to nectary development: the gene is highly expressed in nectary; ectopic expression of it in the Arabidopsis crc-1 mutant rescued the lost nectary (also the carpel and silique defects). We also demonstrated that a MADS-box transcription factor ZjAGAMOUS1 (ZjAG1) is required for the direct activation of ZjCRC expression. Conclusions Taken together, our results not only provide a comprehensive portrait of the jujube nectary, but also pave the way to effective utilization of jujube and other woody crops.

Abstract Background The genomes within organelles are crucial for physiological functions such as respiration and photosynthesis and may also contribute to environmental adaptation. However, the limited availability of genetic resources, particularly mitochondrial genomes, poses significant challenges for in-depth investigations. Results Here, we explored various assembly methodologies and successfully reconstructed the complex organelle genomes of two Rhododendron species: Rhododendron nivale subsp. boreale and Rhododendron vialii. The mitogenomes of these species exhibit various conformations, as evidenced by long-reads mapping. Notably, only the mitogenome of R. vialii can be depicted as a singular circular molecule. The plastomes of both species conform to the typical quadripartite structure but exhibit elongated inverted repeat (IR) regions. Compared to the high similarity between plastomes, the mitogenomes display more obvious differences in structure, repeat sequences, and codon usage. Based on the analysis of 58 organelle genomes from angiosperms inhabiting various altitudes, we inferred the genetic adaptations associated with high-altitude environments. Phylogenetic analysis revealed partial inconsistencies between plastome- and mitogenome-derived phylogenies. Additionally, evolutionary lineage was determined to exert a greater influence on codon usage than altitude. Importantly, genes such as atp4, atp9, mttB, and clpP exhibited signs of positive selection in several high-altitude species, suggesting a potential link to alpine adaptation. Conclusions We tested the effectiveness of different organelle assembly methods for dealing with complex genomes, while also providing and validating high-quality organelle genomes of two Rhododendron species. Additionally, we hypothesized potential strategies for high-altitude adaptation of organelles. These findings offer a reference for the assembly of complex organelle genomes, while also providing new insights and valuable resources for understanding their adaptive evolution patterns.

Abstract In vertebrate spindles, most microtubules are formed via branching microtubule nucleation, whereby microtubules nucleate along the side of pre-existing microtubules. Hepatoma up-regulated protein (HURP) is a microtubule-associated protein that has been implicated in spindle assembly, but its mode of action is yet to be defined. In this study, we show that HURP is necessary for RanGTP-induced branching microtubule nucleation in Xenopus egg extract. Specifically, HURP stabilizes the microtubule lattice to promote microtubule formation from γ-TuRC. This function is shifted to promote branching microtubule nucleation through enhanced localization to TPX2 condensates, which form the core of the branch site on microtubules. Lastly, we provide a high-resolution cryo-EM structure of HURP on the microtubule, revealing how HURP binding stabilizes the microtubule lattice. We propose a model in which HURP stabilizes microtubules during their formation, and TPX2 preferentially enriches HURP to microtubules to promote branching microtubule nucleation and thus spindle assembly.

Abstract Background Lysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer’s disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood. Methods ROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1–TFEB axis on lysosomes in APP/PS1 transgenic mice. Results ROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevation resulted in abundant extracellular Aβ deposition which in turn bound to Aβ receptors and activated RhoA/ROCK1, thus forming a vicious circle of AD pathogenesis. Genetically downregulating ROCK1 lowered its interference with TFEB, promoted TFEB nuclear distribution, lysosomal biogenesis and lysosome-mediated Aβ clearance, and eventually prevented pathological traits and cognitive deficits in APP/PS1 mice. Conclusion In summary, our results provide a mechanistic insight into the critical role of ROCK1 in lysosomal regulation and Aβ clearance in AD by acting as a novel upstream serine kinase of TFEB.

Abstract The study of vessel trajectories (VTs) holds significant benefits for marine route management and resource development. VT segmentation serves as a foundation for extracting vessel motion primitives and enables analysis of vessel manoeuvring habits and behavioural intentions. However, existing methods relying on predefined behaviour patterns face high labelling costs, which hinder accurate pattern recognition. This paper proposes a self‐supervised vessel trajectory segmentation method (SS‐VTS), which segments VTs based on their inherent spatio‐temporal semantics. SS‐VTS adaptively divides VTs into cells of optimal size. Then, it extracts split points on different semantic levels from the multi‐dimensional feature sequence of the VTs using self‐supervised learning. Finally, spatio‐temporal distance fusion module is performed on split points to determine change points and obtain VT segments with multiple semantics. Experiments on a real automatic identification system datasets show that SS‐VTS achieves state‐of‐the‐art segmentation results compared to seven baseline methods.

Abstract Background Research investigating the potential link between gingival microvascular blood flow and inflammatory status is scarce. This study aims to assess color doppler flow imaging (CDFI) and micro-flow imaging (MFI) as tools for the assessment of gingival papilla blood flow (GPBF) and to examine their diagnostic utility as a noninvasive means of detecting gingival bleeding. Methods CDFI and MFI were used to assess the GPBF grade (0–4) of 140 anterior gingival papilla sites in advanced periodontitis patients. Correlations between GPBF grades and periodontal characteristics were examined, and diagnostic performance as a means of predicting bleeding on probing (BOP) was examined using receiver operating characteristic curves. Results GPBF grades 0 and 1 assessed by the MFI were 14.29% and 15.71% respectively, lower than the 28.57% and 24.29% assessed by the CDFI. In contrast, MFI detected a higher frequency of GPBF grade 2 sites (40.71%) relative to CDFI (22.14%). The CDFI and MFI provided consistent results in 62.14% of the sites, while the MFI demonstrated higher ratings in rest 37.86% of the sites. A significant positive correlation was detected between GPBF grade and the modified gingival index (MGI), bleeding index (BI), BOP, and probing depth (PD). It showed high accuracy for CDFI or MFI to diagnosing BOP with a sensitivity of 80.51% and 96.43% and a specificity of 77.27% and 57.14%, respectively. Area under the receiver operator characteristic curve values when predicting BOP based on the GPBF grade determined using CDFI and MFI approaches 0.887 (95% CI 0.833–0.942) and 0.917 (95% CI 0.862–0.972), respectively, and there were no significant differences between these values (Z = − 1.502, p = 0.133). Conclusions Both MFI and CDFI can be employed for the evaluation of GPBF, and MFI is better suited to detecting mild inflammation. Trial registration ChiCTR2200066021 (Date of registration: 22/11/2022).

Introduction: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. Objectives: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. Methods: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. Results: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. Conclusions: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.

The sensitivity of grain boundary (GB) cracks often limits the high-temperature plasticity of superalloys. The 750 ℃ tensile deformation of fine-grained Ni-Co based wrought superalloys was observed in situ using a scanning electron microscope (SEM) equipped with an electron backscatter diffraction (EBSD) probe to clarify the texture formation and GB response. The GB stress concentration depends on the grain orientation and slip system alignment on both sides. This reflects the ability of GBs to cope with deformation incompatibility. This study provides valuable insights for predicting the failure of polycrystalline superalloys and offers new ideas for microstructure evaluation and GB design.

Perovskite materials (ABO3) possess a wealth of elements selectable and exhibit a diverse range of octahedral transformations. The emergence of high-entropy perovskite ceramics provides a fresh perspective for advancing the field of wave-absorbing materials. In this study, we concentrate on the wet chemical synthesis of a high-entropy perovskite oxide, Sr(Cr0.2Mn0.2Fe0.2Co0.2Ni0.2)O3, and investigate its crystal structure, microstructure, chemical composition, magnetic properties, and microwave absorbing capabilities. The results indicate that when sintered at a temperature of 1,350 °C, the sample achieves a minimum reflection loss of −54.0 dB at a frequency of 9.68 GHz, accompanied by a maximum effective absorption bandwidth (EAB) of 7.44 GHz at the thickness of 1.8 mm. The high-entropy design of the B-site induces distortions of oxygen vacancy and octahedral structure of the perovskite material. This leads to the fine tuning of its dielectric and magnetic properties, thereby endowing perovskite with excellent electromagnetic wave absorption capabilities. Consequently, perovskite emerges as a promising new electromagnetic wave absorption material with significant potential.

Abstract Background In the context of a gradual increase in aging, improving the mental health of the elderly is particularly vital for coping with aging. Leveraging data from the 2020 China Family Panel Studies, this study rigorously examines the influence of short video on the mental health of the elderly. Methods We use a multiple linear regression model to investigate the influence of short video usage on the mental health of the elderly. To address endogeneity concerns, this study employs two-stage least squares and propensity score matching to estimate the impact of short video usage on the mental health of the elderly. Results The empirical analysis reveals a substantive and statistically significant enhancement in the mental health of elderly people attributable to the use of short videos. To ensure the reliability and robustness of our estimations, a comprehensive battery of robustness tests is conducted, all of which consistently support the conclusion of a positive association between short video usage and improved mental health among the elderly. Furthermore, the results of the heterogeneity analysis suggest that short videos have less of an impact on elderly males and individuals with higher levels of education. The results of the mechanism analysis indicate that the use of short videos can enhance the mental health of elderly individuals by positively impacting the intergenerational relationships between them and their children, as well as their leisure consumption habits. Conclusions This study can provide policy inspiration for the government to improve the mental health of the elderly and achieve active aging.

Abstract LiInSe2 crystals are promising semiconductor materials for neutron detectors due to the large neutron capture cross-sectional area of the specific isotopes (6Li) and high charge transport properties. However, the optoelectronic performance fails to reach the expected level due to the difficulty of controlling the crystal defects. Herein, we modulate the stoichiometric ratio to control the type of defects in single LiInSe2 crystals grown by the vertical Bridgman method. The UV‒vis–NIR transmission results indicate that the band gap of the yellow colored Li1.01In1Se2 sample is close to ~ 2.83 eV at room temperature, and this value is consistent with the theoretical band gap of LiInSe2 (~ 2.86 eV). Photoluminescence (PL) spectroscopy was used to analyze the defect concentration. The results indicate that the defect types in the yellow Li1.01In1Se2 single crystal are VSe + and LiIn 2−; these result from the introduction of excess Li and the suppression of the adverse defects in InLi 2+ and VLi −. These results demonstrate a feasible route for obtaining high-quality yellow 6LiInSe2 crystals and promote the application of 6LiInSe2 neutron detectors.

Abstract Late spring frosts, occurring after spring phenological events, pose a dire threat to tree growth and forest productivity. With climate warming, earlier spring phenological events have become increasingly common and led to plants experiencing more frequent and severe frost damage. However, the effect of late spring frosts after leaf-out on subsequent flowering phenology in woody species remains unknown. Utilizing 572,734 phenological records of 640 species at 5024 sites from four long-term and large-scale in situ phenological networks across the Northern Hemisphere, we show that late spring frosts following leaf-out significantly delay the onset of the subsequent flowering by approximately 6.0 days. Late-leafing species exhibit greater sensitivity to the frosts than early-leafing species, resulting in a longer delay of 2.5 days in flowering. Trees in warm regions and periods exhibit a more pronounced frost-induced flowering delay compared to those in cold regions and periods. A significant increase in the frequency of late spring frost occurrence is observed in recent decades. Our findings elucidate the intricate relationships among leaf-out, frost, and flowering but also emphasize that the sequential progression of phenological events, rather than individual phenological stages, should be considered when assessing the phenological responses to climate change.

Abstract Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.

Abstract Objectives This study aimed to compare the temperature rise, time consuming and cut quality of apicectomy using three different methods. Materials and methods Twenty-four single-rooted teeth were collected and divided into four groups operating apicectomy with a NINJA tip of a piezoelectric device (G1), a diamond bur with 300,000 rpm (G2), and Er: YAG laser at 200 mJ/ 30 Hz (G3) as well as 250 mJ/ 30 Hz (G4). The temperature elevation and time were recorded and the cut quality was evaluated via stereomicroscope and scanning electronic microscopy (SEM). Results The temperature increases for G1 was significantly higher than for G2. However, there was no significant difference between G1 and G2 with laser groups respectively. The median time for apicectomy was: 100.14s for G1, 22.65s for G2, 33.58s for G3, and 21.80s for G4. G1 is the most time-consuming group and there was no statistically significance in the comparisons with G2, G3 and G4. Cut quality was assessed by crack occurrence, smear layer formation and dentinal tubules exposed. The percentage of cracked teeth in G1 and G2 was 33.33% and for laser groups the percentage was 16.67% each. SEM showed that no smear layer formed and almost all dentinal tubules were exposed on resected surfaces for G3&G4, surfaces from G2 were partly covered by smear layer, and surfaces from G1 were fully covered by smear layer and with no dentinal tubules exposed. Conclusions Er: YAG laser and conventional rotary instruments were safe and efficient for apicectomy and with a better cut quality when compared with piezoelectric equipment. Er: YAG laser could be a promising technique for apicectomy and further studies are necessary, especially larger sample in vivo investigations, to verify the feasibility of Er: YAG laser in endodontic surgery.

Abstract Drawing inspiration from the state‐of‐the‐art object detection framework YOLOv8, a new model termed adverse weather net (ADWNet) is proposed. To enhance the model's feature extraction capabilities, the efficient multi‐scale attention (EMA) module has been integrated into the backbone. To address the problem of information loss in fused features, Neck has been replaced with RepGDNeck. Simultaneously, to expedite the model's convergence, the bounding box's loss function has been optimized to SIoU loss. To elucidate the advantages of ADWNet in the context of adverse weather conditions, ablation studies and comparative experiments were conducted. The results indicate that although the model's parameter count increased by 18.4%, the accuracy for detecting rain, snow, and fog in adverse weather conditions improved by 22%, while the FLOPs (floating point operations) decreased by 5%. The results of the comparison experiments conducted on the WEDGE dataset show that ADWNet outperforms other object detection models in adverse weather in terms of accuracy, model parameters and FLOPs. To validate ADWNet's real‐world efficacy, data was extracted from a car recorder under adverse conditions on highways, visual inference was conducted, and its accuracy was demonstrated in interpreting real‐world scenarios. The config files are available at https://github.com/Xinyun‐Feng/ADWNet.

Abstract Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1–Nrf2–PHB2 pathway, thereby contributing to the cognitive decline in DE.

Abstract The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.

Abstract Background Endocrine function in patients with type 2 diabetes (T2DM) typically differs from those with normal glucose tolerance (NGT). However, few epidemiologic studies have explored how these differences impact the association between exposure to polychlorinated biphenyls (PCBs) and vitamin D levels. Methods This study included 1,705 subjects aged 18–79 years from the Henan Rural Cohort [887 NGT and 818 T2DM]. Linear regression was applied to evaluate the associations between PCB exposure and vitamin D levels. Quantile g-computation regression (QG) and Bayesian kernel machine regression (BKMR) were applied to evaluate the impact of PCB mixtures on vitamin D levels. Interaction effects of ΣPCBs with HOMA2-%β and HOMA2-IR on vitamin D levels were assessed. Results Plasma ΣPCBs was positively associated with 25(OH)D2 in the NGT group (β = 0.060, 95% CI: 0.028, 0.092). Conversely, in T2DM group, ΣPCBs was negatively associated with 25(OH)D3 and 25(OH)D (β = -0.049, 95% CI: -0.072, -0.026; β = -0.043, 95% CI: -0.063, -0.023). Similarly, both QG and BKMR analysis revealed a negative association between PCB mixture exposure and vitamin D levels in the T2DM group, contrary to the results observed in the NGT groups. Furthermore, the negative association of ΣPCBs with 25(OH)D2 and 25(OH)D disappeared or changed to a positive association with the increase of HOMA2-%β levels. Conclusions These findings suggest that decreased β cell function may exacerbate the negative effects of PCB exposure on vitamin D levels. Recognizing T2DM patients’ sensitivity to PCBs is vital for protecting chronic disease health.

Abstract Background Gliomas are the highly aggressive brain tumor and also the most devastating human tumors. The latent TGF binding proteins (LTBP) had been found to be involved in malignant biological process and could be used as potent biomarkers in several solid tumors. While the role of LTBP family in human glioma remain to be elucidated. Methods Normalized gene expression and corresponding clinical data of 2407 gliomas samples in public datasets were downloaded from Gliovis. Kaplan–Meier methods and Cox regression analysis was used for survival analyses.Western blot (WB) and Immunohistochemical (IHC) testing were employed to test LTBPs protein level in 154 gliomas samples. Correlation between LTBP2 expression and immune infiltration was evaluated by immunofluorescence (IF) and IHC in glioma tissues. CCK8 and flow cytometric analysis were used to detect the effect of LTBP2 on glioma cells. Orthotopic glioma- mouse models were utilized to evaluate effects in vivo. Results LTBP2 mRNA level was dramatically higher in glioma samples compared with non-tumor brain tissues in XENA-TCGA_GTEx, Gill and Gravendeel datasets (all P

Abstract Background Accurately classifying primary bone tumors is crucial for guiding therapeutic decisions. The National Comprehensive Cancer Network guidelines recommend multimodal images to provide different perspectives for the comprehensive evaluation of primary bone tumors. However, in clinical practice, most patients’ medical multimodal images are often incomplete. This study aimed to build a deep learning model using patients’ incomplete multimodal images from X-ray, CT, and MRI alongside clinical characteristics to classify primary bone tumors as benign, intermediate, or malignant. Methods In this retrospective study, a total of 1305 patients with histopathologically confirmed primary bone tumors (internal dataset, n = 1043; external dataset, n = 262) were included from two centers between January 2010 and December 2022. We proposed a Primary Bone Tumor Classification Transformer Network (PBTC-TransNet) fusion model to classify primary bone tumors. Areas under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the model’s classification performance. Results The PBTC-TransNet fusion model achieved satisfactory micro-average AUCs of 0.847 (95% CI: 0.832, 0.862) and 0.782 (95% CI: 0.749, 0.817) on the internal and external test sets. For the classification of benign, intermediate, and malignant primary bone tumors, the model respectively achieved AUCs of 0.827/0.727, 0.740/0.662, and 0.815/0.745 on the internal/external test sets. Furthermore, across all patient subgroups stratified by the distribution of imaging modalities, the PBTC-TransNet fusion model gained micro-average AUCs ranging from 0.700 to 0.909 and 0.640 to 0.847 on the internal and external test sets, respectively. The model showed the highest micro-average AUC of 0.909, accuracy of 84.3%, micro-average sensitivity of 84.3%, and micro-average specificity of 92.1% in those with only X-rays on the internal test set. On the external test set, the PBTC-TransNet fusion model gained the highest micro-average AUC of 0.847 for patients with X-ray + CT. Conclusions We successfully developed and externally validated the transformer-based PBTC-Transnet fusion model for the effective classification of primary bone tumors. This model, rooted in incomplete multimodal images and clinical characteristics, effectively mirrors real-life clinical scenarios, thus enhancing its strong clinical practicability.

Abstract Chemotherapeutic drugs, such as cisplatin (cis-dichlorodiamineplatinum [II], cDDP) and 5-fluorouracil (5Fu), are widely used in transarterial chemoembolization (TACE), which is a standard therapy for patients with hepatocellular carcinoma (HCC). Chemoresistance is a major cause of TACE treatment failure in HCC patients. Our previous studies have identified the expression levels of miR-101 responsive genes, such as EED, EZH2, STMN1 and JUNB, exhibit significant correlation with the occurrence and progression of HCC, while the role of miR-101 responsive gene signatures in the chemoresistance of HCC treatment remains unclear. In this study, we identified ubiquitin-coupled enzyme E2D1 (UBE2D1) as a crucial regulatory factor in the chemoresistance of HCC, which is a direct target of miR-101 and exhibits significant correlation with miR-101-responsive gene signatures. The bioinformatics analysis showed the expression of UBE2D1 was significantly increased in HCC tissues and was closely correlated with the poor prognosis. In addition, we analyzed the role of miR-101/UBE2D1 axis in regulating chemo-sensitive of HCC cells. Our results showed that miR-101 increases the DNA damage and apoptosis of HCC cells by inhibiting the expression of UBE2D1, which in turn increases the sensitivity of HCC cells to cDDP and 5Fu both in vitro and in vivo. Therefore, simultaneous assessment of miR-101 and UBE2D1 expression levels might provide an effective approach in preselecting HCC patients with survival benefit from TACE treatment. Moreover, further elucidation of the underlying molecular mechanisms of the miR-101/UBE2D1 axis could provide novel insight for targeted therapy of HCC.

Abstract Honey vaults are useful tools for password management. A vault usually contains usernames for each domain, and the corresponding passwords, encrypted with a master password chosen by the owner. By generating decoy vaults for incorrect master password attempts, honey vaults force attackers with the vault’s storage file to engage in online verification to distinguish the real vaults, thus thwarting offline guessing attacks. However, sophisticated attackers can acquire additional information, such as personally identifiable information (PII) and partial passwords contained within the vault from various data breaches. Since many users tend to incorporate PII in their passwords, attackers may utilize PII to distinguish the real vault. Furthermore, if attackers may learn partial passwords included in the real vault, it can exclude numerous decoy vaults without the need for online verification. Indeed, both leakages pose serious threats to the security of the existing honey vault schemes. In this paper, we explore two attack variants of the inspired attack scenario, where the attacker gains access to the vault’s storage file along with acquiring PII and partial passwords contained within the real vault, and design a new honey vault scheme. For security assurance, we prove that our scheme is secure against one of the aforementioned attack variants. Moreover, our experimental findings suggest enhancements in security against the other attack. In particular, to evaluate the security in multiple leakage cases where both the vault’s storage file and PII are leaked, we propose several new practical attacks (called PII-based attacks), building upon the existing practical attacks in the traditional single leakage case where only the vault’s storage file is compromised. Our experimental results demonstrate that certain PII-based attacks achieve a 63–70% accuracy in distinguishing the real vault from decoys in the best-performing honey vault scheme (Cheng et al. in Incrementally updateable honey password vaults, pp 857–874, 2021). Our scheme reduces these metrics to 41–50%, closely approaching the ideal value of 50%.

Abstract SM9 was established in 2016 as a Chinese official identity-based cryptographic (IBC) standard, and became an ISO standard in 2021. It is well-known that IBC is suitable for Internet of Things (IoT) applications, since a centralized processing of client data (e.g. IoT cloud) is often done by gateways. However, due to limited computation resources inside IoT devices, the performance of SM9 becomes a bottleneck in practical usage. The existing SM9 implementations are often CPU-based, with relatively low latency and low throughput. Consequently, a pivotal challenge for SM9 in large-scale applications is how to reduce the latency while maximizing throughput for numerous concurrent inputs. After a systematic analysis of the SM9 algorithms, we apply optimization techniques including precomputation, resource caching and parallelization to reduce the overhead of SM9. In this work, we introduce the first practical implementation of SM9 and its underlying SM9_P256 curve on GPU. Our GPU implementation combines multiple algorithms and low-level optimizations tailored for GPU’s single instruction, multiple threads architecture in order to achieve high throughput for SM9. Based on these, we propose GAPS, a high-performance Cryptography as a Service (CaaS) for SM9. GAPS adopts a heterogeneous computing architecture that flexibly schedules the inputs across two implementation platforms: a CPU for the low-latency processing of sporadic inputs, and a GPU for the high-throughput processing of batch inputs. According to our benchmark, GAPS only takes a few milliseconds to process a single SM9 request in idle mode. Moreover, when operating in its batch processing mode, GAPS can generate 2,038,071 private keys, 248,239 signatures or 238,001 ciphertexts per second. The results show that GAPS scales seamlessly across inputs of different sizes, preliminarily demonstrating the efficacy of our solution.

Abstract This paper adopts the “baseline scenario method” to construct a comprehensive model for calculating and reducing carbon emissions generated by employee travel, including the accounting of carbon emissions from commuting and business travel, as well as the assessment of green travel for carbon reduction. The study employs methods such as questionnaires and on-site interviews to collect travel data from employees of a research institute in Beijing as a case study. The results show that employees’ commuting methods are diverse, with the subway being the primary mode of travel; however, business travel generates higher carbon emissions, particularly among employees with higher education levels. The research concludes that the model proposed in this paper provides a framework for preliminary carbon emission estimation, but to improve the accuracy of the estimates, more variables and factors need to be considered, and the limitations of the model are pointed out. The research findings have significant implications for policy and institutional practices, suggesting the adoption of more targeted measures to reduce the use of high-carbon-emission travel methods and to encourage the use of green travel options. With the continuous advancement of data collection technologies in the future, it will be possible to further establish a more refined carbon emission accounting model and obtain more accurate and comprehensive travel data, thereby providing solid data support for the development of more effective carbon reduction strategies and policies.

Leaves are the main organ for photosynthesis and organic synthesis in cotton. Leaf shape has important effects on photosynthetic efficiency and canopy formation, thereby affecting cotton yield. Previous studies have shown that LMI1 (LATE MERISTEM IDENTITY1) is the main gene regulating leaf shape. In this study, the LMI1 gene was inserted into the 35S promoter expression vector, and cotton plants overexpressing LMI1 (OE) were obtained through genetic transformation. Statistical analysis of the biological traits of the T1 and T2 populations showed that compared to the wild type (WT), OE plants had significantly larger leaves, thicker stems and significantly greater dry weight. Furthermore, plant sections of the main vein and petiole showed that the numbers of cells in those tissues of OE plants were significantly greater. In addition, RNA-seq analysis revealed the differential expression of genes related to gibberellin synthesis and NAC gene family (genes containing the NAC domain) between the OE and WT plants, suggesting that LMI1 is involved in secondary wall formation and cell proliferation, which promotes stem thickening. Moreover, Gene Ontology (GO) analysis revealed enrichment in the terms of calcium ion binding, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed enrichment in the terms of fatty acid degradation, phosphatidylinositol signal transduction system, and cAMP (cyclic adenosine monophosphate) signal pathway. These results suggested that LMI1 OE plants are responsive to gibberellin hormone signals, and have altered messenger signals (cAMP, Ca2+) which amplify this function, to promote stronger aboveground vegetative growth. This study found the LMI1 greatly increased the vegetative growth in cotton, which is the basic requirement for higher yield.

The pipe curtain structure method (PSM) is a novel construction method to control ground deformation strictly. Compared with the traditional pipe-roofing and pipe jacking method, the connection between pipes in large spacings using PSM is widely acknowledged as a unique construction procedure. Further study on this connection procedure is needed to resolve similar cases in that the pipes are inevitably constructed on both sides of existing piles. Cutting the steel plate during the connection procedure is the first step, which is crucial to control the safety and stability of the surrounding environment and existing structures. The deformation mechanism and limit support pressure of the cutting steel plate during the connection between pipes in large spacings are studied in this paper, relying on the undercrossing Yifeng gate tower project of Jianning West Road River Crossing Channel in Nanjing, China. A modified 3D wedge-prism failure model is proposed using the 3D discrete element method. Combined with Terzaghi loose earth pressure theory and the limit equilibrium theory, the analytical solutions for the limit support pressure of the excavation face of the cutting steel plate are derived. The modified 3D wedge-prism failure model and corresponding analytical solutions are categorised into two cases: (a) unilateral cutting scheme, and (b) bilateral cutting scheme. The analytical solutions for the two cases are verified from the numerical simulation and in-situ data and compared with the previous solutions. The comparative analysis between the unilateral and bilateral cutting schemes indicates that the bilateral cutting scheme can be adopted as a priority. The bilateral cutting scheme saves more time and induces less ground deformation than the unilateral one due to the resistance generated from the superimposed wedge. In addition, the parametric sensitivity analysis is carried out using an orthogonal experimental design. The main influencing factors arranged from high to low are the pipe spacing, the cutting size, and the pipe burial depth. The ground deformation increases with the increased cutting size and pipe spacing. The pipe burial depth slightly affects the ground deformation if the other two factors are minor. Cutting steel plates in small sizes, excavating soil under low disturbance, and supporting pipes for high frequency can effectively reduce the ground surface subsidence.

Abstract Apoptosis is a genetically programmed form of cell death that is substantially conserved across the evolutionary tree. Apoptotic cell elimination includes recognition, phagocytosis, and degradation. Failure to clear apoptotic cells can ultimately cause a series of human diseases, such as systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and cancer. Consequently, the timely and effective removal of apoptotic cells is crucial to maintaining the body's homeostasis. GPCRs belong to the largest membrane receptor family. Its intracellular domain exerts an effect on the trimer G protein. By combining with a variety of ligands, the extracellular domain of G protein initiates the dissociation of G protein trimers and progressively transmits signals downstream. Presently, numerous G protein‐coupled receptors (GPCRs) have been identified as participants in the apoptosis signal transduction pathway and the apoptotic cell clearance pathway. Therefore, studies on the mechanism of GPCRs in the clearance of apoptotic cells is important for the development of GPCRs therapeutics.

Abstract Background This study aims to review the clinical characteristics, therapeutic response and outcome of idiopathic pulmonary hemosiderosis (IPH), and discover the risk factors for recurrence in children with IPH, which will be helpful for the early diagnosis and reasonable treatment of this disease. Methods Children with a diagnosis of IPH were enrolled in the study. Clinical data of the children were collected and analysed. Results A total of 32 patients with regular follow-up after diagnosis were included in this study. Anaemia, cough and haemoptysis constituted the most common initial symptoms of the disease, and the incidences were 90.6%, 75% and 56.2%, respectively. The mean gap between the onset of symptoms and diagnosis was 5 (0.25-36) months. Most of the children experienced remission (complete and partial remission) over the course of 6 months of treatment, but 19 of the children experienced relapse. The causes of disease recurrence included respiratory tract infection (37.5%), corticosteroid (CS) reduction (18.8%), and irregular medication (6.3%). Interestingly, we found that children with history of allergy (HR 4.255, 1.107–16.356) tended to experience disease recurrence (p = 0.01). Conclusions Cough and anaemia are the most common symptoms in children with IPH. The recurrence rate of this disease is high, and respiratory tract infection is the most common cause of its recurrence. High-dose CS impluse therapy cannot reduce the recurrence rate of the disease. Allergic history was an import factor associated with disease recurrence. Trial registration This study is a retrospective and observational study, which does not involve human specimens or clinical intervention. Therefore, clinical trial registration is not required, and there is no clinical trial number. However, the study was approved by the Institutional Review Board/Ethics Committee affiliated with West China Second University Hospital, Sichuan University (Ethics review number 2022074).

Asphalt pavement repair areas affect pavement performance and service levels. It is necessary to distinguish the repair areas from normal sections. Based on vehicle vibration signals, this study identified ten pavement repair areas and divided them into four cases by factors including length and form in conjunction with the driving approach. Additionally, time domain analysis, frequency analysis, and probability distribution analysis were used to form the characteristics of the repair cases as well as the normal sections. It was found that the maximum value, extreme deviation, standard deviation in the time domain, maximum amplitude in the frequency domain, and peak of the probability density curve would serve as judgment indexes. A framework for identifying the repair areas was also established based on the five indexes. By validation, the overall accuracy can reach 95.0%, demonstrating a strong generalization capability.

Abstract Background Occupational Bloodborne Exposures (OBEs) are incidents where healthcare workers come into contact with blood or other potentially infectious materials, leading to risks of transmitting bloodborne pathogens. Nursing students, often in direct contact with patients, face heightened risks due to their duties. Methods First, we conducted a cross-sectional survey using a OBEs questionnaire to explore the knowledge, attitudes, practices, and needs regarding OBEs among nursing students. Subsequently, we used a randomized controlled trial (RCT) to compare the impact of the Presentation-Assimilation-Discussion (PAD) method with the traditional lecture-based learning (LBL) method on OBEs education for nursing students. Pre-test, post-test, and retention test were used to observe the teaching effectiveness, and the students’ feedback on the teaching method was also observed. Results In the cross-sectional survey, we found that nursing students lacked sufficient knowledge and management skills regarding OBEs but recognized the importance of standard precautions and expressed a desire for systematic OBEs training during their education and internships. In the RCT, the total, theoretical, and practical scores of the PAD and LBL groups were comparable in the pre-test (56.70 ± 3.47 vs. 56.40 ± 3.95, 33.09 ± 3.39 vs. 33.33 ± 2.44, 23.61 ± 4.66 vs. 23.07 ± 4.84, p > 0.05). After training, the PAD model demonstrated an advantage over the LBL model in immediate total (84.25 ± 4.06 vs. 78.95 ± 4.23, p 0.05). The PAD group benefited more across various learning dimensions but reported a higher study load. Conclusions Our study reveals that the PAD model could be a valuable approach for teaching OBEs to nursing students.

Abstract Background Agricultural irrigation is an important practice to safeguard crops against drought and enhance grain yield in arid regions. The Hexi Corridor, known as a classic arid region, faces significant pressure on agricultural production and food security due to the scarcity of water resources. There is an urgent need to investigate agricultural water use of the irrigated regions. Water use efficiency (WUE), defined as the ratio of gross primary productivity (GPP) to actual evapotranspiration (ET), serves as a valuable indicator linking carbon assimilation and water loss. It enables the quantification of areas where water can be utilized more effectively. However, the long-term spatiotemporal dynamics of WUE and driving mechanism in the irrigated areas of the Hexi Corridor remain unclear. Results This study used GPP calculated by a light use efficiency model (EF-LUE), ET estimated by an ETMonitor model and irrigated cropland maps across China (IrriMap_CN) to examine the spatiotemporal dynamics of irrigated cropland WUE and its controlling factors in the Hexi Corridor from 2001 to 2018. The results are as following: (1) The average annual WUE was approximately 1.34 ± 0.38 g C kg−1 H2O yr−1, with an increasing trend of 0.012 g C kg−1 H2O yr−1, and faster growth observed during 2011–2018 compared to 2001–2010. (2) The contribution of GPP to WUE trends and WUE interannual variability (IAV) was greater than that of ET. (3) The dominant climatic factors of WUE IAV in the Hexi Corridor were SPEI, precipitation, and soil moisture. (4) The standardized Structural Equation Model (SEM), incorporating the relationship between WUE and factors such as water, energy, NDVI, and water-saving irrigation, explained 81% of the variation in irrigated cropland WUE. Here, biological factors (GPP and NDVI) were the primary factors influencing WUE variability, and water-saving irrigation had a stronger indirect effect than climate factors (water and energy) on variation in WUE. Conclusions Our findings offer valuable theoretical insights into the mechanisms governing the interaction between the carbon and water of irrigated cropland, guiding the management of water resources and land in agricultural practices within the Hexi Corridor.

Abstract Chronic lymphocytic leukemia (CLL) presents with heterogeneous clinical outcomes, suggesting varied underlying pathogenic mechanisms. This study aims to elucidate the impact of T follicular helper (Tfh) cells on CLL progression and prognosis. Gene expression profile data for CLL were collected from GSE22762 and GSE39671 datasets. Patients were divided into high and low groups using Tfh levels using the optimal cutoff value based on overall survival (OS) and time-to-first treatment (TTFT). Differential expression analysis was performed between these groups, followed by co-expression network analysis and single-sample Gene Set Enrichment Analysis (ssGSEA). Marker genes of Tfh cells were used to construct prognostic models. Additionally, 40 CLL patients were recruited and categorized based on median Tfh levels. Marker gene expression was assessed using RT-qPCR and Western Blot, and immune cell levels were determined through flow cytometry. The high group showed better prognosis compared to the low group. Among the 1121 differentially expressed genes identified, five co-expression networks were constructed, with the turquoise module showing the highest correlation with Tfh cells. Genes within this module significantly participate in cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, and natural killer cell mediated cytotoxicity. Tfh cells were significantly negatively correlated with activated B cells and positively correlated with Tregs. The Random Survival Forest (RSF) model identified 10 marker genes, and further analysis using Lasso regression and nomogram selected CLEC4A, RAE1, CD84, and PRDX1 as prognostic markers. In the high group, levels of CLEC4A and RAE1 were higher than in the low group, whereas CD84 and PRDX1 were lower. Flow cytometry revealed that the level of activated B cells in the high Tfh group was significantly lower than in the low Tfh group, while the level of Tregs is significantly higher in the high Tfh group. This study seeks to contribute to a more detailed understanding of the pathogenesis of CLL, delving into the prognostic significance of Tfh.

Abstract Understanding the spatiotemporal characteristics and comprehensive service capabilities of various ecosystem services is crucial for maintaining regional ecosystem security, and clarifying the driving mechanisms of ecosystem services plays a guarantee for achieving regional sustainable development. Based on the ecological issues of Shanxi Province (SXP) in China, an assessment system covering eight targeted ecosystem services were constructed to quantitatively analyze the spatio-temporal patterns and contribution rates of driving factors. The water conservation, sand fixation, environment purification and habitat quality in the Loess Hills of western SXP have improved, with significant increase in hotspots. The comprehensive service capacity of ecosystem services in the Fenwei Basin (central SXP) has deteriorated, and the coldspots have expanded. The water conservation, carbon storage, habitat quality and recreation culture in the Yanshan-Taihang Mountains (eastern SXP) were enhanced, while product supply, carbon storage and environment purification were deteriorated. Land use is the dominant influencing factor on product supply. Water and soil conservation, sand fixation, and environment purification are dominated by climate factors. Carbon storage, habitat quality and recreation culture are influenced by underlying surface conditions. The current study provided a research paradigm, which will help the government with appropriate management policies to ensure the effectiveness of ecological protection and restoration, and offers insights for facilitating ecological sustainability and economic transformation in resource-based regions worldwide.

Abstract Background Gastrointestinal mesenchymal stromal tumors (GISTs) are a group of intramural tumors that exhibit a wide range of morphologies. Dysfunction or loss of interstitial cells of Cajal (ICCs) is correlated with the disorders of gastrointestinal motility. At present, the characterization and molecular mechanisms underlying the role of ICCs in GIST are still not clear. Methods The GSE162115 dataset from Gene Expression Omnibus database was processed using Seurat package for quality control, data normalization, and cell clustering. Differential expression and functional enrichment analyses were performed using the FindAllMarkers function and clusterProfiler package. Cellular heterogeneity was assessed by CytoTRACE and potential regulatory mechanisms of ICCs in GISTs were investigated using SCENIC. Cellular communication was inferred and analyzed applying the CellChat package. Results Eight clusters were identified based on 34,861 cells. Intra-tumor samples had a higher proportion of ICCs than peri-tumor. ICCs were related to cell cycle and glycolytic activity in intra-tumor samples, while those in peri-tumor samples were involved in immune response. Further analysis identified four ICC subgroups (subcluster 1–4), of which subcluster 3 showed the most typical stem cell properties and interacted with the rest of the cells through the MIF-CD74 (CD44) protein. Conclusion This study analyzed the heterogeneity and stem cell properties of ICCs in GISTs, revealing the molecular mechanisms and potential therapeutic targets for GISTs.

Abstract Organic semiconductors (OSCs) are featured by weak spin-orbit coupling due to their light chemical element composition, which enables them to maintain spin orientation for a long spin lifetime and show significant potential in room-temperature spin transport. Carrier mobility and spin lifetime are the two main factors of the spin transport performance of OSCs, however, their ambiguous mechanisms with molecular structure make the development of spintronic materials really stagnant. Herein, the effects of halogen substitution in bay-annulated indigo-based polymers on carrier mobility and spin relaxation have been systematically investigated. The enhanced carrier mobility with an undiminished spin lifetime contributes to a 3.7-fold increase in spin diffusion length and a record-high magnetoresistance of 8.7% at room temperature. By analyzing the spin-orbit coupling and hyperfine interaction, it was found that the distance of the substitution site from the conjugated center and the nitrogen atoms in the molecules play crucial roles in spin relaxation. Based on the above results, we proposed a molecular design strategy of halogen substitution far from conjugate center to enhance spin transport efficiency, presenting a promising avenue for advancing the field of organic spintronics.

Abstract Metal micro/nanoparticle ink-based printed circuits have shown promise for promoting the scalable application of flexible electronics due to enabling superhigh metallic conductivity with cost-effective mass production. However, it is challenging to activate printed metal-particle patterns to approach the intrinsic conductivity without damaging the flexible substrate, especially for high melting-point metals. Here, we report a pressure-constrained sonication activation (PCSA) method of the printed flexible circuits for more than dozens of metal (covering melting points from room temperature to 3422 °C) and even nonmetallic inks, which is integrated with the large-scale roll-to-roll process. The PCSA-induced synergistic heat-softening and vibration-bonding effect of particles can enable multilayer circuit interconnection and join electronic components onto printed circuits without solder within 1 s at room temperature. We demonstrate PCSA-based applications of 3D flexible origami electronics, erasable and foldable double-sided electroluminescent displays, and custom-designed and large-area electronic textiles, thus indicating its potential for universality in flexible electronics.

Abstract Carbon peaking and achieving carbon neutrality have emerged as pivotal strategic imperatives in China. These objectives not only drive a shift in production, lifestyle, and consumption patterns but also illuminate a path towards a comprehensive green metamorphosis in China’s economic and social development landscape. The distinctive nature of museums as quintessential public edifices, requiring sustained regulation of temperature and humidity alongside attracting substantial foot traffic, positions them as crucial pioneers in the pursuit of carbon peaking and neutrality. It is essential for museums to leverage their leadership and advocacy roles to catalyze low-carbon construction practices across society. This study delves into the energy dynamics specific to the museum sector, delving into the recycling of exhibition materials, methodologies for carbon footprint assessments of visitors and museum staff, and the establishment of a standardized carbon emission accounting framework tailored to the museum industry. Through meticulous examination of representative cases and subsequent analysis, this research delineates decarbonization strategies, offering indispensable technical scaffolding for carbon assessment and emission reduction efforts within the museum realm.

Abstract Background Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. Results In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis. Conclusions This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.

Abstract Background This study investigated the clinical value of breast magnetic resonance imaging (MRI) radiomics for predicting axillary lymph node metastasis (ALNM) and to compare the discriminative abilities of different combinations of MRI sequences. Methods This study included 141 patients diagnosed with invasive breast cancer from two centers (center 1: n = 101, center 2: n = 40). Patients from center 1 were randomly divided into training set and test set 1. Patients from center 2 were assigned to the test set 2. All participants underwent preoperative MRI, and four distinct MRI sequences were obtained. The volume of interest (VOI) of the breast tumor was delineated on the dynamic contrast-enhanced (DCE) postcontrast phase 2 sequence, and the VOIs of other sequences were adjusted when required. Subsequently, radiomics features were extracted from the VOIs using an open-source package. Both single- and multisequence radiomics models were constructed using the logistic regression method in the training set. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and precision of the radiomics model for the test set 1 and test set 2 were calculated. Finally, the diagnostic performance of each model was compared with the diagnostic level of junior and senior radiologists. Results The single-sequence ALNM classifier derived from DCE postcontrast phase 1 had the best performance for both test set 1 (AUC = 0.891) and test set 2 (AUC = 0.619). The best-performing multisequence ALNM classifiers for both test set 1 (AUC = 0.910) and test set 2 (AUC = 0.717) were generated from DCE postcontrast phase 1, T2-weighted imaging, and diffusion-weighted imaging single-sequence ALNM classifiers. Both had a higher diagnostic level than the junior and senior radiologists. Conclusions The combination of DCE postcontrast phase 1, T2-weighted imaging, and diffusion-weighted imaging radiomics features had the best performance in predicting ALNM from breast cancer. Our study presents a well-performing and noninvasive tool for ALNM prediction in patients with breast cancer.

Abstract The transcription factor WRKYs play pivotal roles in the adapting to adverse environments in plants. Prior research has demonstrated the involvement of OsWRKY70 in resistance against herbivores and its response to abiotic stress. Here, we reported the functional analysis of OsWRKY70 in immunity against fungal diseases and cold tolerance. The results revealed that OsWRKY70 was induced by various Magnaporthe oryzae strains. Knock out mutants of OsWRKY70, which were generated by the CRISPR/Cas9 system, exhibited enhanced resistance to M. oryzae. This was consistent with fortifying the reactive oxygen species (ROS) burst after inoculation in the mutants, elevated transcript levels of defense-responsive genes (OsPR1b, OsPBZ1, OsPOX8.1 and OsPOX22.3) and the observation of the sluggish growth of invasive hyphae under fluorescence microscope. RNA sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) validations demonstrated that differentially expressed genes were related to plant-pathogen interactions, hormone transduction and MAPK cascades. Notably, OsbHLH6, a key component of the JA signaling pathway, was down-regulated in the mutants compared to wild type plants. Further investigation confirmed that OsWRKY70 bound to the promoter of OsbHLH6 by semi-in vivo chromatin immunoprecipitation (ChIP). Additionally, the loss-function of OsWRKY70 impaired cold tolerance in rice. The enhanced susceptibility in the mutants characterized by excessive ROS production, elevated ion leakage rate and increased malondialdehyde content, as well as decreased activity of catalase (CAT) and peroxidase (POD) under low temperature stress was, which might be attributed to down-regulation of cold-responsive genes (OsLti6b and OsICE1). In conclusion, our findings indicate that OsWRKY70 negatively contributes to blast resistance but positively regulates cold tolerance in rice, providing a strategy for crop breeding with tolerance to stress.

Abstract Extrusion-based three-dimensional (3D) printing of gelatin (Gel) is crucial for fabricating bone tissue engineering scaffolds via additive manufacturing. However, the thermal instability of Gel remains a persistent challenge, as it tends to collapse at mild temperatures. Current approaches often involve simply mixing Gel particles with various materials, resulting in biomaterial inks that lack uniformity and have inconsistent degradation characteristics. In this study, acetic acid was used to dissolve Gel and polycaprolactone (PCL) separately, producing homogeneous Gel/PCL dispersions with optimal pre-treatment performance. These dispersions were then combined and hybridized with nano-hydroxyapatite (n-HA) to create a composite printing ink. By evaluating the printability of the ink, the optimal conditions were identified: a n-HA concentration of 50% (w/w), a printing temperature of 10–15 ℃, a printing pressure of 2.5 bar, and a printing speed of 7 mm/s. The resulting biomaterial inks, with a composition of 25% Gel, 25% PCL, and 50% n-HA, demonstrated excellent printability and stability, along with significantly enhanced mechanical properties. As a result, 3D scaffolds with high printability and shape fidelity can be printed at room temperature, followed by deep freezing at -80 ℃ and cross-linking with vanillin. The Gel-based composite scaffolds demonstrated excellent biocompatibility, cell adhesion, cell viability and nano-hydroxyapatite absorption in vitro. Additionally, in vivo experiments revealed that the bioactive scaffold biodegraded during implantation and significantly promoted bone regeneration at the defect site. This provides a promising strategy for treating bone defects in clinical setting. In conclusion, the Gel/PCL/n-HA biomaterial inks presented here offer an innovative solution for extrusion bioprinting in the field of bone tissue engineering. Graphical Abstract

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

ABSTRACTBackground Pneumococcal vaccines are effective in preventing pneumococcal diseases in adults. The evaluation of the antibodies persistence to the 23-valent pneumococcal polysaccharide vaccine (PPV23) could provide evidence on PPV23 revaccination.Research design and methods Adults aged ≥ 60 years were selected and vaccinated with PPV23 in Shanghai, and followed up for 5 years with blood samples collection of a 1-year interval. The geometric mean concentrations (GMC) of the IgG against 23 pneumococcal serotypes covered by PPV23 were detected using enzyme-linked immunosorbent assay. The antibodies to 23 pneumococcal serotypes among different groups was analyzed using statistical analysis.Results Overall, 517 participants completed all six visits over a 5-year period (2013–2018). The GMC of 23 serotypes in adults aged ≥ 60 years decreased slowly after PPV23 vaccination compared to baseline pre-vaccination (P

To meet the cross-domain surfaced communication requirements of underwater information in cross-domain cooperative operations, a low-power cross-domain communication buoy system was designed by taking advantage of the buoy’s flexible deployment, long-term concealment, and flexible payload characteristics. This system mainly supported deep-sea deployment at great depths and long-term silent watch and concealed cross-domain communication upon activation. Additionally, it could autonomously destruct critical components according to preset instructions, thus avoiding the exposure risk of surfaced communication on underwater platforms such as submarines, and it is relatively easy to deploy and sustain. Test results indicate that the designed system features high pressure resistance, low power consumption, and certain scalability, offering good prospects for application.

Evidence regarding the association between cancer and heart failure (HF) is scarce. This study is to investigate the association between HF and cancer and explore the prognostic value of NT-proBNP in cancer patients. This cohort study used National Health and Nutrition Examination Survey data from 1999 to 2018 and linked mortality information until 2019. We included all participants with valid answer to questions regarding self-reported cancer and HF. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% CIs. Our study included data from 54,847 adult participants. During a median (IQR) follow-up of 9.6 (4.0–15.1) years, 7674 deaths were recorded. HF was associated with an increased occurrence of cancer after propensity score matching (OR = 1.46, 95% CI: 1.17–1.82, p < 0.001). Cancer was associated with a higher occurrence of HF (OR = 1.33, 95% CI: 1.11–1.59, p = 0.002). Kaplan–Meier survival analysis over 10 years revealed the shortest survival in patients with both HF and cancer (log-rank p < 0.0001). Importantly, NT-proBNP was significantly higher in cancer patients, no matter whether with known HF (p < 0.01). In cancer patients without HF, NT-proBNP higher than 51.51 pg/mL was associated with shorter survival (log-rank p < 0.0001). Findings from this cohort study suggest that HF is significantly associated with cancer. NT-proBNP was higher in cancer patients, with significant prognostic value in cancer patients.

Abstract The human insulin gene modified with a C-peptide was synthesized according to the plant-preferred codon, and a fusion gene expression vector of insulin combined with green fluorescent protein (GFP) was constructed. The optimization of the flax callus culturing was undertaken, and a more efficient Agrobacterium-mediated genetic transformation of the flax hypocotyls was achieved. The critical concentration values of hygromycin on the flax hypocotyl development, as well as on its differentiated callus, were explored by the method of antibiotic gradient addition, and the application of antibiotic screening for the verification of positive calluses was assessed. The fusion gene of insulin and GFP was successfully inserted into the flax genome and expressed, as confirmed through polymerase chain reaction and Western blotting. In conclusion, we have established a flax callus culture system suitable for insulin expression. By optimizing the conditions of the flax callus induction, transformation, screening, and verification of a transgenic callus, we have provided an effective way to obtain insulin. Moreover, the herein-employed flax callus culture system could provide a feasible, cheap, and environmentally friendly platform for producing bioactive proteins. Graphical Abstract

Abstract Background Oxidative stress (OS) is one of the major causes of ovarian aging and dysfunction. Indole-3-propionic acid (IPA) is an indole compound derived from tryptophan with free radical scavenging and antioxidant properties, and thus may have potential applications in protecting ovarian function, although the exact mechanisms are unknown. This study aims to preliminarily elucidate the potential mechanisms of IPA that benefit ovarian reserve function through network pharmacology, molecular docking, and experimental verification. Methods The related protein targets of IPA were searched on SwissTargetPrediction, TargetNet, BATMAN-TCM, and PharmMapper databases. The potential targets of diminished ovarian reserve (DOR) were identified from OMIM, GeneCards, DrugBank, and DisGeNET databases. The common targets were uploaded directly to the STRING database to construct PPI networks. We then performed GO and KEGG enrichment analysis on the targets. Subsequently, molecular docking and molecular dynamics simulation were used to validate the binding conformation of IPA to candidate targets. Furthermore, we carried out in vitro experiments to validate the prediction results of network pharmacology. Results We identified a total of 61 potential targets for the interaction of IPA with DOR. The PPI network topological parameter analysis yielded 13 hub genes for DOR treatment. The GO biological process enrichment analysis identified 293 entries, mainly enriched in aging, signal transduction, response to hypoxia, negative regulation of apoptotic process, and positive regulation of cell proliferation. The KEGG enrichment analysis mainly included lipid and atherosclerosis, progesterone-mediated oocyte maturation, AGE-RAGE, relaxin, estrogen, and other signaling pathways. The molecular docking further revealed the direct binding of IPA with six hub proteins including NOS3, AKT1, EGFR, PPARA, SRC, and TNF. In vitro experiments showed that IPA pretreatment attenuated H2O2-induced cellular oxidative stress damage, while IPA exerted cytoprotective and antioxidant damage effects by regulating the six hub genes and antioxidant proteins. Conclusion We systematically illustrated the potential protective effects of IPA against DOR through multiple targets and pathways using network pharmacology, and further verified the cytoprotective effect and antioxidant properties of IPA through in vitro experiments. These findings provide new insights into the targets and molecular mechanisms whereby IPA improves DOR.