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Background Ischemia with nonobstructive coronary arteries (INOCA) has high morbidity, mortality, and poor quality of life. Metabolic syndrome (MetS) is a complex of multiple cardiac metabolic risk factors, significantly increasing the risk of major adverse cardiovascular events in INOCA patients. The study aimed to investigate the aggravating effect of MetS on left ventricular (LV) deformation and function impairment in INOCA patients. Materials and methods This study collected 104 INOCA patients (INOCA [MetS−]: n = 56; INOCA [MetS+]: n = 48) and 41 sex- and age-matched controls. LV function, indexed myocardial energetic efficiency (MEEI), and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured among the three groups. The independent factors of reduced MEEI and impaired LV function and strain parameters for all INOCA patients were assessed using multivariable linear regression analyses. Results In contrast to the INOCA (MetS-) group, the indexed LV stroke volume (LVSVI) (49.57 ± 11.58 mL/m2 vs. 42.58 ± 12.23 mL/m2, p = 0.007), MEEI [0.85(0.70–1.03) ml/s/g vs. 0.75(0.54–0.91) ml/s/g, p = 0.045] and LV global longitudinal peak strain (GLPS) (− 13.26 ± 2.86% vs. -10.95 ± 3.93%, p = 0.001) reduced in the INOCA (MetS+) group. Compared with the controls, LV GLPS decreased in the INOCA (MetS-) group (− 15.14 ± 2.83% vs. −13.26 ± 2.86%, p = 0.017). MetS was negatively associated with LVSVI, MEEI, and LV GLPS (all p

Abstract Background Although childhood maltreatment (CM) is widely recognized as a transdiagnostic risk factor for various internalizing and externalizing psychological disorders, the neural basis underlying this association remain unclear. The potential reasons for the inconsistent findings may be attributed to the involvement of both common and specific neural pathways that mediate the influence of childhood maltreatment on the emergence of psychopathological conditions. Methods This study aimed to delineate both the common and distinct neural pathways linking childhood maltreatment to depression and aggression. First, we employed Network-Based Statistics (NBS) on resting-state functional magnetic resonance imaging (fMRI) data to identify functional connectivity (FC) patterns associated with depression and aggression. Mediation analyses were then conducted to assess the role of these FC patterns in the relationship between childhood maltreatment and each outcome. Results The results demonstrated that FC within the default mode network (DMN) and between the cingulo-opercular network (CON) and dorsal attention network (DAN) mediated the association between childhood maltreatment and aggression, whereas FC within the reward system and between the CON and the reward system mediated the link between childhood maltreatment and depression. Conclusions We speculate that the control system may serve as a transdiagnostic neural basis accounting for the sequela of childhood maltreatment, and the attention network and the reward network may act as specific neural basis linking childhood maltreatment to depression and aggression, respectively.

Abstract Increasing evidence points toward an essential role for complement activation in the pathogenesis of diabetic kidney disease (DKD). However, the precise molecular mechanisms remain unclear, and the pathway predominantly contributing to complement activation in DKD is of particular interest. In this study, the glomerular proteome, especially the profiles of the complement proteins, was analyzed in kidney biopsies from 40 DKD patients and 10 normal controls using laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS). The glomerular abundances of three proteins related to classical pathway (CP) (C1q, C1r, C1s), five proteins related to alternative pathway (AP) (CFB, CFH, CFHR1, CFHR3, CFHR5), one common protein related to CP and lectin pathway (LP) (C4), and six proteins related to terminal complement pathway (C3, C5, C6, C7, C8, C9) were significantly increased in DKD. Notably, none of the proteins unique to the lectin complement pathway, including mannose-binding lectin (MBL) and its associated proteins, were detected in DKD glomeruli. Furthermore, the glomerular complement proteins of CP and AP were positively correlated with glomerular pathological grades and proteinuria, and negatively correlated with eGFR in DKD patients. Our results highlight a critical role for complement activation of the CP and AP, rather than the LP, in DKD progression.

Abstract This study explores the effect of risk factors on the progression of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) to α-synucleinopathies in a Chinese cohort. Patients with iRBD were enrolled and assessed for environmental factors and lifestyle using standardized structured questionnaires at baseline. All patients were prospectively followed for phenoconversion monitoring. The cumulative incidence was estimated using survival analysis. Of 155 iRBD enrolled in the cohort, follow-up information was available in 141 patients. The phenoconversion rate was 16.3% after 3 years, 27.6% after 5 years, and 57.2% after 10 years. Eighteen participants converted within 3 years, 27 converted within 5 years, and 36 converted within 10 years. IRBD with positive family history of parkinsonism had an increased risk of being converted to α-synucleinopathies, while tea drinking was associated with a decreased phenoconversion risk. Our findings shed light on a potential application of tea drinking in modifying iRBD progression.

Abstract A comprehensive understanding of the intrinsic piezoelectric anisotropy stemming from diverse chemical and physical factors is a key step for the rational design of highly anisotropic materials. We performed high-throughput calculations on tetragonal ABO3 perovskites to investigate the overall characteristics of their piezoelectricity and the interplay between lattice, displacement, polarization, and elasticity. Among the screened 123 types of perovskites, the structural tetragonality is naturally divided into two categories: normal tetragonal (c/a ratio 1.17), exhibiting distinct chemical features, ferroelectric, elastic, and piezoelectric properties. Charge analysis revealed the mechanisms underlying polarization saturation and piezoelectricity suppression in the super-tetragonal region, which also produces an inherent contradiction between high piezoelectric coefficient d 33 and large piezoelectric anisotropy ratio |d 33/d 31|. Both the polarization axis and elastic softness direction are strongly correlated to piezoelectric anisotropy, which jointly determines the direction of maximum longitudinal piezoelectric response d 33. The validity and deficiencies of the widely utilized |d 33/d 31| ratio for representing piezoelectric anisotropy were reevaluated.

Abstract Plasma biomarkers have great potential in the screening, diagnosis, and monitoring of Alzheimer’s disease (AD). However, findings on their associations with cerebral perfusion and structural changes are inconclusive. We examined both cross-sectional and longitudinal associations between plasma biomarkers and cerebral blood flow (CBF), gray matter (GM) volume, and white matter (WM) integrity. Forty-eight AD patients whose diagnosis was supported by amyloid-β (Aβ) PET received measurement of plasma biomarkers with a single molecular array, including Aβ42, phosphorylated tau 181 (P-tau181), neurofilament light (NfL), total tau (T-tau), and glial fibrillary acidic protein (GFAP), and both baseline and one-year follow-up magnetic resonance imaging, including pseudo-continuous arterial spin labeling, T1-weighted imaging, and diffusion tensor imaging. Correlations were found between regional CBF and several plasma biomarkers, with Aβ42 showing the strongest correlation with CBF in the left inferior temporal gyrus (r = 0.507, p = 0.001). Plasma P-tau181 and GFAP levels were correlated with GM volume in the posterior cingulate gyrus and the bilateral hippocampus and right middle temporal gyrus, respectively. Decreased CBF and GM volume in regions vulnerable to AD, such as the posterior cingulate gyrus, inferior parietal lobule and hippocampus, could be predicted by the levels of specific plasma biomarkers. Most biomarkers, except Aβ42, showed extensive correlations with longitudinal WM disruption. Plasma biomarkers exhibited varied correlations with brain perfusion, GM volume, and WM integrity and predicted their longitudinal changes in AD patients, suggesting their potential to reflect functional and structural changes and to monitor pathophysiological progression in the brain.

Societal Impact Statement The strangler fig is known for its hemiepiphytic growth form and conspicuous strangling behavior in the tropics worldwide. It also plays an important role in providing ecological functions in tropical urban ecosystems. This study reveals strangler figs tend to colonize large trees with suitable microsites in a large tropical botanical garden and cause some negative effects on their hosts. We advocate balanced management strategies considering ecological functions, potential risks, and overall values of stranglers and their hosts. These results provide a scientific basis for us to develop better practices for plant management in urban green spaces (especially botanical gardens with high plant biodiversity) in tropical urban ecosystems. Summary Strangler figs colonize trees in tropical cities, which contribute to a unique urban ecology and enrich local ecological functions. Understanding ecological associations between strangler figs and their host trees can improve green space management in tropical urban ecosystems. We investigated 9282 trees growing in the Xishuangbanna Tropical Botanical Garden and then analyzed the diversity, characteristics, and network of strangler figs and their host trees. We found 13 strangler fig species (319 individuals) widely colonized 67 host species, with palm hosts bearing 52% of all strangler individuals. Strangler figs had a high colonization rate in large trees with appropriate microsites (e.g., persistent palm petioles and the fork of mature trees with rough trunks). Leaf nitrogen and phosphorus content of hosts decreased significantly after strangler figs' aerial roots had entered the ground. The strangler–host network was characterized by relatively high specialization and low nestedness, and simulated management of strangler figs on large hosts and palm hosts could simplify the strangler–host network. Strangler fig colonization can be managed. Planting trees with large diameters at breast height and rough bark can increase the colonization of stranglers, while cutting off aerial roots can inhibit their establishment. The epiphytic stage is the best time to manage strangler figs. We recommend taking into consideration the trade‐offs among ecological functioning, human safety, and the multifaceted value of strangler figs and their host trees and thereby implementing comprehensive management strategies tailored to different contexts for improving green space management in the tropics.

Objective: The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. Methods: An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Results: Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. Conclusions: An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

Abstract Background Pulmonary hypertension (PH) is a severe cardio-pulmonary vascular disease, involves complex molecular mechanism especially during the pathological process of pulmonary vascular remodeling, brings a significant challenge to clinical treatment and thus resulting in high mortality rates. Classic Traditional Chinese medicine formula, Zhishi Xiebai Guizhi Decoction (ZXGD), holds therapeutic potential for PH. In present study, we sought to explore therapeutic potential of ZXGD against PH in rats. Methods We employed a combination methods of chemical profiling, echocardiographic, morphologic measurements, molecular biology, rats models and cultured pulmonary artery smooth muscle cells (PASMCs) to achieve this. Results Eighteen compounds were precisely identified in ZXGD using UHPLC-QTOF-MS/MS. Our data demonstrated ZXGD could alleviate PH by reducing pulmonary artery pressure and alleviating pulmonary vascular remodeling in rats. Specifically, ZXGD was found to intervene in abnormal expansion of PASMCs, thereby attenuating pulmonary vascular remodeling. ZXGD was also observed to modulate expressions of HIF-1α, ROS, and Nrf2 to alleviate hypoxia and oxidative stress. Additionally, ZXGD significantly regulated disorders in pro-inflammatory cytokines, thus mitigating inflammation. Furthermore, ZXGD decreased levels of decadienyl-l-carnitine and LDL-C, while elevating HDL-C and lipid droplet counts, thereby reducing cholesterol and lipid toxicity and preserving mitochondrial function. Importantly, inhibition of HIF-1α reversed expression of key pathological triggers for pulmonary vascular remodeling. Neohesperidin and naringin in ZXGD extract were identified as the primary contributors to its pharmacological effects against PH. Conclusion Altogether, our study empirically explored therapeutic potential and pharmacological mechanisms of ZXGD in treating PH, offering a groundwork for the development of novel anti-PH drugs. Graphical Abstract

Abstract To address the impact of distributed generation (DG) access on the traditional protection configuration methods of distribution networks (DNs) and to facilitate the swift and effective protection of lines by protection devices under fault conditions, an adaptive current protection method for three‐phase short‐circuit faults in active distribution networks (ADNs), based on local information, is proposed. Initially, the applicability issues of traditional protection are examined, and the limitations of the existing protection scheme in ADNs are highlighted. Subsequently, the fault characteristics of ADNs are analysed, taking into account the output characteristics of DGs under short‐circuit faults, which form the foundation for the proposed protection method. Following this, an adaptive current protection method based on local information is introduced, utilizing a dual criterion of phase and magnitude to adjust line protection, with a specific implementation strategy for the protection scheme provided. Finally, the proposed protection scheme is validated using PSCAD/EMTDC simulation software, with results demonstrating that the scheme enables rapid and efficient protection action under fault conditions across the entire line.

Abstract Nitrogen (N) is one of the three major elements required for plant growth and development. It is of great significance to study the effects of different nitrogen application levels on the growth and root exudates of Phlomoides rotata, and can provide a theoretical basis for its scientific application of fertilizer to increase production. In this study, Phlomoides rotata were grown under different nitrogen conditions for two months. Soil and plant analyzer development (SPAD) values, bioaccumulation, root morphology, root exudate composition, nitrogen metabolism enzyme and antioxidant enzyme activity were evaluated. The results showed that compared with CK (no N fertilizer), N2 (CO(NH2)2 80 mg/kg) and N3 (CO(NH2)2 160 mg/kg) through significantly improved the activities of nitrogen metabolism enzyme nitrite reductase (NiR), glutamate dehydrogenase (GDH) and glutamine synthetase (GS), enhanced the nitrogen metabolism process, and increased the accumulation of plant soluble sugars (SS) and soluble protein (SP), thus improving Phlomoides rotata biomass yield. After 60 days of treatment, low nitrogen (N1, CO(NH2)2 40 mg/kg) increased root length, root volume, root surface area, average root diameter, significantly increased the diversity of organic acids in root exudates, and enhanced the activity of antioxidant enzymes to adapt the nitrogen deficiency environment. This study can provide new ideas for understanding the mechanism of nitrogen tolerance in Phlomoides rotata and developing scientific fertilization management strategies for plateau plants and medicinal plants.

Abstract Background Partial stereotactic body radiation therapy (SBRT) targeting hypoxic regions of large tumors (SBRT-PATHY) has been shown to enhance the efficacy of tumor radiotherapy by harnessing the radiation-induced immune response. This approach suggests that reducing the irradiation target volume not only achieves effective anti-tumor effects but also minimizes damage to surrounding normal tissues. In this study, we evaluated the antitumor efficacy of reduced-tumour-area radiotherapy (RTRT) , and explored the relationship between tumor control and immune preservation and the molecular mechanisms underlying of them. Methods In mouse breast cancer models, we compared the anti-tumor effects of RTRT and conventional radiotherapy (CNRT) by assessing tumor growth, metastasis, and survival rates. Additionally, we evaluated the peritumoral tissue damage and the immune microenvironment. The maturation of dendritic cells (DCs) and DNA damage induced by irradiated tumor cells were also assessed in vitro. Results In pre-clinical models, both RTRT and CNRT significantly inhibited primary tumor growth when compared to non-irradiated controls, with no significant difference between RTRT and CNRT. However, RTRT significantly extended survival times in mice, and increased the likelihood of inducing abscopal effects, thereby providing potential for better control of distant metastases. Further investigations revealed that the enhanced efficacy of RTRT may be attributed to the preservation of lymphocytes within the peritumoral tissue, as well as reduced damage to the surrounding skin and circulating lymphocytes. In vitro assays demonstrated that RTRT induced DNA damage and dsDNA in tumor cells, activating the cGAS-STING pathway. RTRT also triggered the release of damage-associated molecular patterns (DAMPs), which synergistically amplified the anti-tumor immune response. Conclusions Our findings suggested that appropriately narrowing the irradiation target volume effectively killed tumor cells while reducing damage to surrounding tissues, and preserving peritumoral lymphocytes. This approach improved the safety of radiotherapy while maintaining its efficacy in tumor control and provided an opportunity for combining high-dose radiotherapy with immunotherapy.

Herein, poly(pentanediamine terephthalamide) (PA5T) homopolymer was synthesized via a salt-forming reaction+solid state polycondensation method using bio-based 1,5-pentanediamine and terephthalic acid as the primary raw materials. To address the issue of its narrower processing window, poly(hexamethylene terephthalamide)(PA6T), which also cannot be melt processed due to the processing window is negative, was introduced into its molecular chain to synthesize poly (pentanediamine/hexanediamine terephthaloyl) (PA5T-co-6T) copolymers. The structures were investigated by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance carbon spectroscopy (13C-NMR). Furthermore, the melting temperature, crystallization temperature, thermal stability, and crystal growth mode of the polymer were tested and analyzed using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and wide-angle x-ray diffraction (WAXD), respectively. The results demonstrate that the crystal growth mode gradually changes from three-dimensional spherical growth to two-dimensional disk-like or three-dimensional spherical growth with the increase of 6T chain segment content. Simultaneously, the crystallization temperature, melting temperature, and crystallization rate of the polymer all showed a trend of decreasing first and then increasing, which was due to the combined effects of the increase in the content of 6T chain segments on the molecular-chain structure and crystal structure of the polymer. Bio-based PA5T-co-6T has excellent heat resistance and a wider processing window than PA5T and PA6T, which possesses great application prospects in the fields of automotive, electronic appliances, and LED optics.

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.

In order to solve the embrittlement problem of welded joint of pipeline steel, this paper proposes to study the influence of Mo on M-A component of the subcritically reheated coarse-grained HAZ (SCGHAZ), and Mo on bainite transformation. Through the welding thermal simulation experiment, two kinds of X80 pipeline steel with different Mo content were set different secondary thermal cycle peak temperatures to simulate the heat affected zone (HAZ). Samples in the SCGHAZ were selected to observe the microstructure, M-A component, microalloy-element distribution and fracture crack trend, and comprehensively analyze the reasons for the deterioration of impact toughness caused by the changes of Mo content. The results show that the increase of Mo content leads to the formation of twinning martensite, which is one of the reasons for the deterioration of toughness. Mo is enriched at the interface of ferrite and M-A component, reducing the binding energy at the interface, resulting in the desorption of M-A component from the matrix, the formation of pores and becoming the nucleation site of cracks, resulting in the generation of micro-cracks and the decrease of toughness.

Abstract Background A deep learning (DL) model that can automatically detect and classify cervical canal and neural foraminal stenosis using cervical spine magnetic resonance imaging (MRI) can improve diagnostic accuracy and efficiency. Methods A method comprising region-of-interest (ROI) detection and cascade prediction was formulated for diagnosing cervical spinal stenosis based on a DL model. First, three part-specific convolutional neural networks were employed to detect the ROIs in different parts of the cervical MR images. Cascade prediction of the stenosis categories was subsequently performed to record the stenosis level and position on each patient slice. Finally, the results were combined to obtain a patient-level diagnostic report. Performance was evaluated based on the accuracy (ACC), area under the curve (AUC), sensitivity, specificity, F1 Score, diagnosis time of the DL model, and recall rate for ROI detection localization. Results The average recall rate of the ROI localization was 89.3% (neural foramen) and 99.7% (central canal) under the five-fold cross-validation of the DL model. In the dichotomous classification (normal or mild vs. moderate or severe), the ACC and AUC of the DL model were comparable to those of the radiologists, and the F1 score (84.8%) of the DL model was slightly higher than that of the radiologists (83.8%) for the central canal. Diagnosing whether the central canal or neural foramen of a slice is narrowed in the cervical MRI scan required an average of 15 and 0.098 s for the radiologists and DL model, respectively. Conclusions The DL model demonstrated comparable performance with subspecialist radiologists for the detection and classification of central canal and neural foraminal stenosis on cervical spine MRI. Moreover, the DL model demonstrated significant timesaving ability.

The purpose of this study was to explore the effect of freeze treatment on the binding characteristics of fillets to flavor substances in fish soup with pickled mustard greens. The study focused on the effects of freeze-thaw treatment and freeze storage on the physicochemical properties of snakehead myofibrillar protein and its binding characteristics to hexanal, octanal, linalool and myrcene. The results showed that after 7 days of storage, the solubility of myofibrillar protein decreased by about 26% in the freeze-thaw group. Compared with the freeze storage group, the oxidation degree and tertiary structural changes of myofibrillar protein were higher and more soluble aggregates were formed in the freeze-thaw group. The solubility of myofibrillar protein decreased by about 33% in the freeze storage group, which showed a more significant decrease compared to the freeze-thaw treatment (P < 0.05), resulting in more insoluble aggregates. The major force for the aggregation of myofibrillar proteins after freezing was non-covalent bonding. Molecular docking results indicated that linalool, hexanal and octanal could bind to myofibrillar proteins through hydrophobic interactions and hydrogen bonds, while the major driving force for the binding of myrcene to myofibrillar proteins was hydrophobic interaction. Freeze treatment reduced the binding capacity of hexanal and octanal to sulfhydryl groups in myofibrillar proteins through hydrogen bonds, improved the surface hydrophobicity of myofibrillar proteins, but increased the binding ability of myrcene and linalool to myofibrillar proteins. Freeze-thaw treatment increased the binding capacity of myofibrillar proteins to myrcene compared with freeze storage treatment. The results of this research provide a theoretical basis and reference for flavor control of frozen prepared fish soup with pickled mustard greens.

Abstract Background Metabolic syndrome (MetS) and coronary artery stenosis (CAS) independently increase the risk of cardiovascular events, while the impact of CAS on left ventricular (LV) function and deformation in MetS patients remains unclear. This study investigates how varying degrees of CAS exacerbate LV function and myocardial deformation in MetS patients. Methods One hundred thirty-one MetS patients who underwent CMR examinations were divided into two groups: the MetS(CAS−) group (n = 47) and the MetS(CAS+) group (n = 84). The MetS(CAS+) group was divided into MetS with non-obstructive CAS(NOCAS+) (n = 30) and MetS with obstructive CAS(OCAS+) group (n = 54). Additionally, 48 age- and sex-matched subjects were included as a control group. LV functional and deformation parameters were measured and compared among subgroups. The determinants of decreased LV global peak strains in all MetS patients were identified using linear regression. The receiver operating characteristic (ROC) curve and logistic regression model (LRM) evaluated the diagnostic accuracy of the degree of CAS for identifying impaired LV strain. Results Compared to MetS(CAS−), MetS(NOCAS+) showed a significantly increased LV mass index (p

Abstract Background The extract from Metasequoia glyptostroboides Hu et Cheng, a rare and endangered species native to China, exhibits numerous biological and pharmacological activities. The species is recalcitrant to rooting during micropropagation, a challenge that has yet to be resolved. In this study, transcriptomic and hormonal analyses were conducted to appreciate the molecular mechanism of adventitious root (AR) formation in optimized rooting conditions. Results The use of 2/5-strength Woody Plant Medium (WPM) significantly promoted AR formation of M. glyptostroboides shoots while the content of endogenous auxin, cytokinins and gibberellins (GAs) varied at different stages of AR formation. Transcriptomic analysis showed the significant up- or down-regulation of differentially expressed genes (DEGs) associated with plant hormone signal transduction and the phenylpropanoid biosynthesis pathway in response to 2/5-strength WPM. DEGs related to the biosynthesis of indole-3-acetic acid, cytokinins and GAs were identified. Transcript factors involved in 13 families were also revealed. A weighted gene co-expression network analysis indicated a strong correlation between hormones and genes involved in plant hormone signal transduction and the phenylpropanoid biosynthetic pathway. Conclusions These results indicate that the AR-promoting potential of 2/5-strength WPM in M. glyptostroboides was due to complex interactions between hormones and the expression of genes related to plant hormone signal transduction and the phenylpropanoid biosynthetic pathway.

Abstract Despite the advances in antibody-guided cell typing and mass spectrometry-based proteomics, their integration is hindered by challenges for processing rare cells in the heterogeneous tissue context. Here, we introduce Spatial and Cell-type Proteomics (SCPro), which combines multiplexed imaging and flow cytometry with ion exchange-based protein aggregation capture technology to characterize spatial proteome heterogeneity with single-cell resolution. The SCPro is employed to explore the pancreatic tumor microenvironment and reveals the spatial alternations of over 5000 proteins by automatically dissecting up to 100 single cells guided by multi-color imaging of centimeter-scale formalin-fixed, paraffin-embedded tissue slide. To enhance cell-type resolution, we characterize the proteome of 14 different cell types by sorting up to 1000 cells from the same tumor, which allows us to deconvolute the spatial distribution of immune cell subtypes and leads to the discovery of subtypes of regulatory T cells. Together, the SCPro provides a multimodal spatial proteomics approach for profiling tissue proteome heterogeneity.

Abstract Background Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although intensive studies and therapeutic approaches, there are limited restorative treatments till now. Human embryonic stem cell (hESCs)-derived cortical neural progenitors have shown great potentials in ischemic stroke in adult brain. However, it is unclear whether they are feasible for cortical reconstruction in immature brain with hypoxic-ischemic encephalopathy. Methods By using embryonic body (EB) neural differentiation method combined with DAPT pre-treatment and quantitative cell transplantation, human cortical neuroblasts were obtained and transplanted into the cortex of hypoxic-ischemic injured brain with different dosages 2 weeks after surgery. Then, immunostaining, whole-cell patch clamp recordings and behavioral testing were applied to explore the graft survival and proliferation, fate commitment of cortical neuroblasts in vitro, neural circuit reconstruction and the therapeutic effects of cortical neuroblasts in HIE brain. Results Transplantation of human cortical neural progenitor cells (hCNPs) in HIE-injured cortex exhibited long-term graft overgrowth. DAPT pre-treatment successfully synchronized hCNPs from different developmental stages (day 17, day 21, day 28) to deep layer cortical neuroblasts which survived well in HIE injured brain and greatly prevented graft overgrowth after transplantation. Importantly, the cortical neuroblasts primarily differentiated into deep-layer cortical neurons and extended long axons to their projection targets, such as the cortex, striatum, thalamus, and internal capsule in both ipsilateral and contralateral HIE-injured brain. The transplanted cortical neurons established synapses with host cortical neurons and exhibited spontaneous excitatory or inhibitory post-synaptic currents (sEPSCs or sIPSCs) five months post-transplantation. Rotarod and open field tests showed greatly improved animal behavior by intra-cortex transplantation of deep layer cortical neuroblasts in HIE injured brain. Conclusions Transplanted hESCs derived cortical neuroblasts survive, project to endogenous targets, and integrate into host cortical neural circuits to rescue animal behavior in the HIE-injured brain without graft overgrowth, providing a novel and safe cell replacement strategy for the future treatment of HIE.

Abstract Subduction zones metamorphic fluids are pivotal in geological events such as volcanic eruptions, seismic activity, mineralization, and the deep carbon cycle. However, the mechanisms governing carbon mobility in subduction zones remain largely unresolved. Here we present the first observations of immiscible H2O-CH4 fluids coexisting in retrograde carbonated eclogite from the Western Tianshan subduction zone, China. We identified two types of fluid inclusions in host ankerite and amphibole, as well as in garnet and omphacite. Type-1 inclusions are water-rich with CH4 vapor, whereas Type-2 are CH4-rich, with minimal or no H2O. The coexistence of these fluid types indicates the presence of immiscible fluid phases under high-pressure conditions (P = 1.3-2.1 GPa). Carbonates in subduction zones can effectively decompose through reactions with silicates, leading to the generation of abiotic CH4. Our findings suggest that substantial amounts of carbon could be transferred from the slab to mantle wedge as immiscible CH4 fluids. This process significantly enhances decarbonation efficiency and may contribute to the formation of natural gas deposits.

Inclusion clusters with a size of several tens of micrometers were found to be inclined to early crack initiation, resulting in an abnormally reduced fatigue life. Fatigue tests were conducted to elucidate crack initiation behaviors of inclusion clusters in nickel-based powder metallurgy (P/M) FGH96 superalloy. The inclusion clusters with varying sizes and shapes located at grain boundaries are composed of Al2O3, MgO and ZrO2 particles. The inclusion cluster with large size within 25–35 μm, small average particle distance within 0–4 μm and large orientation relative to loading direction within 35–66° will be more likely to cause crack initiation. In particular, the inclusion clusters with large size and high aggregation degree experience extruding during processing and subsequent heat-treatments due to the difference in thermal expansion coefficient with the matrix behave multiple cracking before fatigue loading, thereby facilitating crack initiation in the surrounding matrix grains. Moreover, as the main cracking part of inclusion clusters, the Al2O3 particles exhibit self-cracking and interface debonding, owing to higher hardness and poorer deformation coordination degree with matrix compared to other component inclusion particles.

Objectives: As the core component of major equipment, the tooth surface accuracy of gears is ultimately guaranteed by the gear grinding process. The electroplated worm grinding roller is an indispensable precision machining tool for dressing worm grinding wheels, which indirectly plays a decisive role in the machining quality and manufacturing cost of gears. However, the tooth shape of the electroplated worm grinding roller is triangular, which leads to several issues: the adhesion difficulty of abrasive particles at the top of the tooth increases significantly, the distribution of abrasive particles becomes sparse, and the dressing condition deteriorates. The isolated abrasive particles at the top of the tooth resemble a cantilever beam structure and are easily dislodged during the dressing process. As a result, the abrasive particles at the top of the roller tooth fail earlier than those on the sides of the tooth, leading to premature roller wear and scrapping, which seriously affects the manufacturing cost of the gear. To address these issues effectively, this study uses CVD (chemical vapor deposition) reinforced material embedded composite electroplating technology to manufacture worm grinding rollers, guided by the CVD matching theory to improve the grinding stability of the rollers. Methods: First, the equivalent wear model of CVD and diamond abrasive particles is established. Then, the abrasive particle distribution theory model of electroplating worm grinding and dressing rollers is developed using the sector concentric ring model. Next, the CVD matching model is derived through rigorous mathematical formulation. However, since the theoretical model of abrasive particle distribution is complex and difficult to solve, the assignment method is used for more detailed theoretical analysis. Finally, the accuracy of the model is verified through practical applications. Results: (1) The CVD matching quality is closely related to several parameters, such as the relative material properties, electroplating process level, diamond abrasive crystal type characteristics, and roller structure. Among these, material properties, electroplating process level, and abrasive crystal type are relatively fixed. Therefore, in practical engineering applications, emphasis should be placed on the relationship between the number of CVD inserts and the geometric parameters of the worm gear grinding roller structure. (2) When the CVD material is determined, the matching number is primarily influenced by the roller module, with a certain linear negative correlation to the roller module. Additionally, there is a weak negative correlation with the radius R of the CVD arc of the roller, while the relationship with the pressure angle of the machined gear is not significant. (3) When the modulus mn and the arc radius R are both 0.80 mm, the matching number K of CVD in the roller is most suitable between 40 and 50 grains. When the pressure angle or tooth tip arc is too small, the number of CVD inlays should be appropriately increased. Generally, the change in the number of CVD inserts due to the pressure angle is no more than 10%. At the same pressure angle, when R is 0.50, 0.20, and 0.10 mm, the K value is 1.3, 2.2, and 3.3 times that when R is 0.80 mm. (4) The application verification of the trimming roller shows that when the CVD embedding quantity K reaches ROUNDUP (Kmin) or more, the service life of the trimming roller remains largely unchanged with the increase of K. Conversely, when K is reduced, the service life of the trimming roller decreases significantly. When the CVD quantity K decreases by 15%, the service life of the trimming roller is reduced by 17.6%. (5) When dressing the grinding wheel under the same dressing process parameters, the service life of the dressing roller is judged based on the number of dressing cycles after which either grinding burn or tooth profile accuracy deviation occurs. A slight difference of 5% is observed between the actual verification results and the theoretical model results. Based on this, the CVD matching quantity of the roller can be designed according to theoretical calculation results in engineering practice. This ensures proper matching of the tooth tip and side loss of the roller while allowing for a repair margin for failed rollers, effectively reducing tool manufacturing costs. Conclusions: The fan-shaped concentric ring CVD matching model simulates the actual distribution of abrasive particles and CVD inserts in worm grinding rollers and introduces the relative wear performance index between diamond abrasive particles and CVD materials. The established model effectively predicts the top and side wear of CVD grinding rollers, enabling the calculation of the appropriate number of CVD inserts. This helps guide the design of worm gear grinding rollers. The model's accuracy is verified through practical applications, and its results can be applied to optimize the grinding process, reduce tool manufacturing costs, and improve the stability and efficiency of worm gear production.

Chemotherapy-induced cardiotoxicity with subsequent heart failure (HF) is a major cause of morbidity and mortality in cancer survivors worldwide. Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation. To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF, we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive (MISA) that could be delivered locally through an endoscope-guided intrapericardial injection. To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients, we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections. In vitro, we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability, but also inhibited their apoptosis. In vivo, we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation, angiogenesis, and mitochondrial respiration. Additionally, we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system. In general, our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.

Abstract Background Although a high C-reactive protein-to-albumin ratio (CAR) is believed to increase mortality risk, the association between the physical activity (PA), CAR, and mortality among cancer survivors has not been investigated. This study aimed to examine this association among cancer survivors in the United States. Methods This cohort study used data from the National Health and Nutrition Examination Survey from 1999 to 2010. PA was self-reported using the Global Physical Activity Questionnaire, and C-reactive protein and albumin levels were obtained from laboratory data files. Mortality data were obtained by linkage of the cohort database to the National Death Index as of December 31, 2019. The analysis was conducted from November 1 to December 31, 2023. We used Cox proportional hazards multivariable regression to assess hazard ratios (HRs) and 95% confidence interval (CIs) for total and cancer-specific mortality risks attributable to PA and CAR. Results Among 2,232 cancer survivors, 325 (14.6%) reported no PA with a high CAR. During a follow-up of up to 20.75 years (median, 12.3 years; 27,453 person-years), 1,174 deaths occurred (cancer, 335; other, 839). A high CAR was observed to be consistently associated with the highest risks of total (HR, 1.59; 95% CI, 1.37–1.85) and cancer-specific (HR, 2.06; 95% CI, 1.55–2.73) mortality compared with a low CAR in a series of adjusted models. Multivariable models showed that PA was associated with a lower risk of all-cause (HR, 0.60; 95% CI, 0.52–0.69) and cancer-specific (HR, 0.64; 95% CI, 0.49–0.84) mortality compared with no PA. In the joint analyses, survivors with PA ≥ 600 metabolic equivalent min/wk and a low CAR were more likely to reduce the risk of total (HR, 0.41; 95% CI, 0.32–0.51) and cancer-specific (HR, 0.32; 95% CI, 0.20–0.50) mortality by 59% and 68% compared with those with no PA and a high CAR. Conclusion The pairing of adequate PA and a low CAR was significantly associated with reduced all-cause and cancer-related mortality risks.

Abstract Background Treatment options for correcting limb-length discrepancy after limb-salvage reconstruction for proximal tibial osteosarcoma in children have several limitations. Therefore, we aimed to evaluate the feasibility, complications, prognosis, and clinical outcomes of reconstruction using hemiarthroplasty after tumor resection in pediatric patients with proximal tibial osteosarcoma. Methods We conducted a comprehensive retrospective analysis of the data of pediatric patients with osteosarcoma of the proximal tibia who underwent surgery between December 2008 and November 2018 at our center. We enrolled 49 consecutive patients who underwent hemiarthroplasty. The cruciate ligaments of all patients were reconstructed using special spacers, and the medial and lateral collateral ligaments of the knee and joint capsule were reconstructed using a mesh. Postoperatively, if the unequal length of both lower limbs exceeded 4 cm or knee instability occurred, a second-stage surgery was performed for limb lengthening and replacing the distal femoral prosthesis. We analyzed the oncological prognosis, complications of hemiarthroplasty, postoperative stability, and postoperative function. Results The follow-up period ranged between 11 and 159 months, with a median of 84 (62, 129) months. The overall 5-year survival rate was 83.2%. Thirty-nine patients survived at the end of the follow-up period with 34 prostheses (87.2%). The overall prosthesis survival rate was 87.4% after 5 years, indicating the long-term benefits of the procedure. Limb length was measured in 28 adult patients. The average limb-length discrepancy was 33 ± 15 mm with a median of 33 mm (21, 47); the femur and tibia caused a discrepancy of 8.5 ± 9.9 mm and 24.8 ± 15.5 mm, respectively. The patients had 30–135° of knee motion, with a mean of 82 ± 24°. The femoral tibial angle was greater on the affected side than on the healthy side, with a mean difference of 4.5°±3.6°. The Musculoskeletal Tumor Society (MSTS) score was 25 ± 3. Five patients underwent second-stage distal femoral prosthesis replacement, with mean MSTS scores of 24 ± 2 and 28 ± 1 before and after second-stage surgery, respectively. Conclusions Hemiarthroplasty in children reduces limb-length discrepancy in adulthood by rebuilding cruciate ligaments, lateral collateral ligaments, and the joint capsule, thereby improving knee stability.

ObjectiveTo elucidate the bidirectional causal relationship between lipid profiles and colorectal cancer (CRC) by using the two-sample and two-step Mendelian randomization (MR) methods, and to explore the mediating role and proportion of immune cells as intermediary factors. MethodsThe pooled statistical data related to the study were screened, and 179 lipids and CRC were analyzed using two-sample and two-step MR with the inverse variance weighted method. Simultaneously, the causal effect was verified via Bayesian weighted MR. Two-step MR analysis was conducted to determine whether a mediated effect was exerted on immune cell traits. Sensitivity, heterogeneity, and pleiotropy analyses were performed to verify the reliability of the study results. ResultsThe causal relationship between nine lipid traits and CRC was preliminarily identified, and no reverse causal effect was found (P>0.05). The validity of the results was verified via Bayesian weighted MR (P

Abstract Symbiotic nitrogen fixation (SNF) in legume-rhizobia serves as a sustainable source of nitrogen (N) in agriculture. However, the addition of inorganic N fertilizers significantly inhibits SNF, and the underlying mechanisms remain not-well understood. Here, we report that inorganic N disrupts iron (Fe) homeostasis in soybean nodules, leading to a decrease in SNF efficiency. This disruption is attributed to the inhibition of the Fe transporter genes Natural Resistance-Associated Macrophage Protein 2a and 2b (GmNRAMP2a&2b) by inorganic N. GmNRAMP2a&2b are predominantly localized at the tonoplast of uninfected nodule tissues, affecting Fe transfer to infected cells and consequently, modulating SNF efficiency. In addition, we identified a pair of N-signal regulators, nitrogen-regulated GARP-type transcription factors 1a and 1b (GmNIGT1a&1b), that negatively regulate the expression of GmNRAMP2a&2b, which establishes a link between N signaling and Fe homeostasis in nodules. Our findings reveal a plausible mechanism by which soybean adjusts SNF efficiency through Fe allocation in response to fluctuating inorganic N conditions, offering valuable insights for optimizing N and Fe management in legume-based agricultural systems.

Objective: To determine the efficacy and safety of the Yinmei Kuijie decoction combined with 5-aminosalicylic acid (5-ASA) in treating mildly to moderately active ulcerative colitis (UC) under real-world conditions. Methods: This multicenter, prospective, non-randomized, observational study will be conducted in real-world settings. A total of 204 eligible patients will be consecutively enrolled in the study. Patients in the combination treatment group will receive Yinmei Kuijie decoction in combination with 5-ASA, whereas those in the control group will be treated with 5-ASA alone. The primary endpoint will be a clinical response at week 12, defined as a ≥3 point and ≥30% reduction from baseline in the Mayo total score with ≥1 reduction in rectal bleeding or rectal bleeding score = 0 or 1. Secondary efficacy endpoints at week 12 will include health-related quality of life, mucosal healing, and inflammation indicators. Conclusion: The results of this study may provide evidence of the efficacy and safety of Yinmei Kuijie decoction combined with 5-ASA in treating patients with mildly to moderately active UC under real-world principles. The results will provide a basis for further confirmatory studies on the efficacy of Yinmei Kuijie decoction.

Abstract Background Hypertension (HTN) and diabetes mellitus (DM) are two common comorbidities of heart failure with reduced ejection fraction (HFrEF), each of which can cause right ventricular (RV) dysfunction. The aim of this study was to investigate the impact of DM on RV dysfunction and ventricular interdependence in hypertensive HFrEF patients via cardiac magnetic resonance imaging (MRI) feature tracking. Methods This study included 249 patients with HFrEF: 77 HFrEF controls, 97 with hypertensive HFrEF (HTN-HFrEF [DM-]) and 75 with hypertensive HFrEF and comorbid DM (HTN-HFrEF [DM+]). The cardiac MRI-derived biventricular global radial (GRS), circumferential (GCS) and longitudinal (GLS) peak strains were obtained and compared among the groups. Multivariable linear regression and mediation analyses were used to evaluate the effects of DM and left ventricular (LV) strain on RV strain. Results The biventricular GLS and GLS of segments 8, 9 and 14 of the interventricular septum (IVS) decreased gradually from the HFrEF control group to the HTN-HFrEF (DM−) group to the HTN-HFrEF (DM+) group (all P

Abstract Associations between the gut microbiota and Parkinson’s disease (PD) have been widely investigated. However, the replicable biomarkers for PD diagnosis across multiple populations remain elusive. Herein, we performed a meta-analysis to investigate the pivotal role of the gut microbiome in PD and its potential diagnostic implications. Six 16S rRNA gene amplicon sequence datasets from five independent studies were integrated, encompassing 550 PD and 456 healthy control samples. The analysis revealed significant alterations in microbial composition and alpha and beta diversity, emphasizing altered gut microbiota in PD. Specific microbial taxa, including Faecalibacterium, Roseburia, and Coprococcus_2, known as butyrate producers, were notably diminished in PD, potentially contributing to intestinal inflammation. Conversely, genera such as Akkermansia and Bilophila exhibited increased relative abundances. A network-based algorithm called NetMoss was utilized to identify potential biomarkers of PD. Afterwards, a classification model incorporating 11 optimized genera demonstrated high performance. Further functional analyses indicated enrichment in pathways related to neurodegeneration and metabolic pathways. These findings illuminate the intricate relationship between the gut microbiota and PD, offering insights into potential therapeutic interventions and personalized diagnostic strategies.

Abstract Background To explore the association of long non-coding RNA (lncRNA) SNHG1/ miR-195 axis with type 2 diabetes mellitus (T2DM) and islet function. Methods The expression of SNHG1 and miR-195 was measured in T2DM patients and in healthy subjects. Correlation between indciators was evaluated using Pearson correlation analysis. INS-1 cells were used to perform the cell function assays. Insulin secretion by INS-1 was detected using ELISA. Cell counting kit-8 (CCK-8) and flow cytometry was used to detect cell proliferation and apoptosis. Luciferase report assay was to used to verify the target of SNHG1. Results The expression of SNHG1 was increased and miR-195 level was decreased in the serum of T2DM patients. Both SNHG1 and miR-195 could be biomarkers for T2DM diagnosis. The fasting plasma glucose (FPG) and HbA1c were positively related to SNHG1 and negatively related to miR-195. SNHG1 inhibited insulin secretion, and cell proliferation and promoted apoptosis of INS-1 cells via binding to miR-195. Conclusions Detection of SNHG1 and miR-195 might predict T2DM. SNHG1 could suppress proliferation and insulin secretion, but promote apoptosis of INS-1 cells via sponging miR-195.

Abstract Background Neonatal septic shock represents a critical and life-threatening condition that necessitates immediate and personalized interventions. Prior research endeavors have been undertaken to inform the optimization of neonatal septic shock management, yet substantial heterogeneity prevails in the selection, measurement, and reporting of outcomes across relevant studies. The heterogeneity in outcome selections and measures impedes the comparability of results and the synthesis of evidence, thus contributing to suboptimal utilization of research findings. This protocol presents the methodology for identifying and developing a Core Outcome Set for Neonatal Septic Shock Management (COS-NSS), intended for use in both research and routine clinical practice. A rigorous four-stage approach will be employed to develop the COS-NSS. In Stage 1, a scoping review will be conducted to compile a list of currently reported outcomes for neonatal septic shock management. Stage 2 will involve an expert stakeholder meeting using a semi-structured discussion approach to elucidate all identified outcomes and outcome domains, as well as to gather any additional outcomes. Moving to Stage 3, a two-round e-Delphi survey involving a wide variety of stakeholders will be undertaken to elicit diverse perspectives on the level of importance assigned to each proposed outcome. Finally, in Stage 4, the results of the Delphi study will be discussed in a consensus meeting to determine and agree on the final list of outcomes that will constitute the COS-NSS. Discussion The stagewise approach integrates research evidence with multi-stakeholder perspectives to establish standardized outcomes that would improve consistency across neonatal septic shock trials. The development and uptake of the COS-NSS will facilitate effective comparison of studies, allowing for study synthesis and generation of high-quality evidence, thus ultimately fostering enhanced medical care for neonates suffering from septic shock. Trial registration Core Outcome Measures in Effectiveness Trials (COMET) Initiative database registration: 2766 . Registered on July 19th, 2023.

The fine modeling of the lunar gravity field is a fundamental task for establishing lunar altitude references, conducting research on lunar interior structure, and other scientific endeavors. The lunar gravity field model constructed solely based on spacecraft orbit data has limited spatial resolution, making it challenging to meet the demands of fine gravity field research. The acquisition of high-resolution terrain models presents new opportunities for the study of precise lunar gravity fields. This paper reviews the current status and advancements in fine lunar gravity field modeling, including research efforts and evaluation methods for global lunar gravity field models, principles and technologies for fine gravity field modeling, as well as related research outcomes. On this basis, this paper systematically summarizes the key theoretical issues and technical challenges in the theory of lunar gravity field modeling based on high-resolution terrain models. These include data updating, error correction in high-frequency gravity field modeling, calculation efficiency, and the series divergence problem in spherical harmonic analysis. In addition, future research directions are discussed. This work will provide references for gravity field research on the Moon and other terrestrial planets.

This study examines market and future-level sentiment in the Chinese agricultural futures market, distinguishing between contagious and idiosyncratic sentiment. Our analysis reveals that agricultural future-level sentiment is significantly affected by market-level sentiment and domestic stock market sentiment, particularly during bullish market conditions, while global stock market sentiment has minimal impact. Furthermore, we find that both market and future-level sentiment strongly and positively influence futures returns, with contagious and idiosyncratic sentiment exerting favorable influences, particularly in bullish markets. Our findings provide clear evidence of sentiment's impact on agricultural futures returns, offering valuable insights for regulators to identify potential market bubbles and implement effective sentiment regulation measures.

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Due to the heterogeneity of nodes and edges, heterogeneous network embedding is a very challenging task to embed highly coupled networks into a set of low-dimensional vectors. Existing models either only learn embedding vectors for nodes or only for edges. These two methods of embedding learning are rarely performed in the same model, and they both overlook the internal correlation between nodes and edges. To solve these problems, a node and edge joint embedding model is proposed for Heterogeneous Information Networks (HINs), called NEJE. The NEJE model can better capture the latent structural and semantic information from an HIN through two joint learning strategies: type-level joint learning and element-level joint learning. Firstly, node-type-aware structure learning and edge-type-aware semantic learning are sequentially performed on the original network and its line graph to get the initial embedding of nodes and the embedding of edges. Then, to optimize performance, type-level joint learning is performed through the alternating training of node embedding on the original network and edge embedding on the line graph. Finally, a new homogeneous network is constructed from the original heterogeneous network, and the graph attention model is further used on the new network to perform element-level joint learning. Experiments on three tasks and five public datasets show that our NEJE model performance improves by about 2.83% over other models, and even improves by 6.42% on average for the node clustering task on Digital Bibliography & Library Project (DBLP) dataset.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Abstract Dental implant restoration shows an effective method for the rehabilitation of missing teeth. The failure rate of periodontal implants in patients with chronic periodontitis is associated with periodontal flora, inflammation, and long-term periodontal bone resorption caused by chronic periodontitis. However, the therapeutic effects of dental implant restoration on inflammation in patients with chronic periodontitis have not addressed. The purpose of this study is to evaluate the risk indicators for inflammation, bone loss and implant failure in patients with chronic periodontitis. A total of 284 patients with dental implant restoration were recruited and divided into periodontally healthy patients (n = 128) and chronic periodontitis patients (n = 156). Periodontal indices including probing depth (PD), sulcus bleeding index (SBI), plaque index (PLI), gingival bleeding (GIL) and bleeding on probing (BOP) were compared in two groups. Inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) levels at baseline, 6 and 12 months after surgery, and the implant survival rate at 12 months after surgery, as well as the risk factors associated with failure of dental implant were also assessed. Outcomes demonstrated that patients in the chronic periodontitis group had higher values of periodontal indices than those in the periodontally healthy group. All inflammatory parameters in the chronic periodontitis group were higher than those in the periodontally healthy group and negatively associated with the chronic periodontal index (CPI) in chronic periodontitis patients. Chronic periodontitis patients had higher the prevalence of mucositis and peri-implantitis than patients with healthy periodontium. Implant diameter, length and design was associated with the risk of implant failure for chronic periodontitis patients receiving dental implant. The cumulative implant failure rate and incidence of implant fractures for chronic periodontitis patients at 12 months after surgery were 12.10% and 7.23% (p

Abstract Background It remains unclear whether the association between dyslipidemia status and triglyceride-glucose (TyG) index with myocardial damage varies in the context of type 2 diabetes mellitus (T2DM). This study aimed to determine the differential effects of dyslipidemia status and TyG index on left ventricular (LV) global function and myocardial microcirculation in patients with T2DM using cardiac magnetic resonance (CMR) imaging. Methods A total of 226 T2DM patients and 72 controls who underwent CMR examination were included. The T2DM group was further categorized into subgroups based on the presence or absence of dyslipidemia (referred to as T2DM (DysL+) and T2DM (DysL-)) or whether the TyG index exceeded 9.06. CMR-derived LV perfusion parameters, remodeling index, and global function index (GFI) were assessed and compared among groups. A multivariable linear regression model was employed to evaluate the effects of various variables on LV myocardial microcirculation, remodeling index, and GFI. Results The LV GFI sequentially decreased in controls, T2DM (DysL-), and T2DM (DysL+) groups (p

Abstract Background The cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers. Methods A partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model’s robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold. Results In the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction). Conclusions NALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY.

Abstract Evidences illustrate that cell senescence contributes to the development of pulmonary arterial hypertension. However, the molecular mechanisms remain unclear. Since there may be different senescence subtypes between PAH patients, consistent senescence-related genes (SRGs) were utilized for consistent clustering by unsupervised clustering methods. Senescence is inextricably linked to the immune system, and the immune cells in each cluster were estimated by ssGSEA. To further screen out more important SRGs, machine learning algorithms were used for identification and their diagnostic value was assessed by ROC curves. The expression of hub genes were verified in vivo and in vitro. Transcriptome analysis was used to assess the effects of silence of hub gene on different pathways. Three senescence molecular subtypes were identified by consensus clustering. Compared with cluster A and B, most immune cells and checkpoint genes were higher in cluster C. Thus, we identified senescence cluster C as the immune subtype. The ROC curves of IGF1, HOXB7, and YWHAZ were remarkable in both datasets. The expression of these genes was increased in vitro. Western blot and immunohistochemical analyses revealed that YWHAZ expression was also increased. Our transcriptome analysis showed autophagy-related genes were significantly elevated after silence of YWHAZ. Our research provided several prospective SRGs and molecular subtypes. Silence of YWHAZ may contribute to the clearance of senescent endothelial cells by activating autophagy.

Abstract Strain engineering plays an important role in tuning electronic structure and improving catalytic capability of biocatalyst, but it is still challenging to modify the atomic-scale strain for specific enzyme-like reactions. Here, we systematically design Pt single atom (Pt1), several Pt atoms (Ptn) and atomically-resolved Pt clusters (Ptc) on PdAu biocatalysts to investigate the correlation between atomic strain and enzyme-like catalytic activity by experimental technology and in-depth Density Functional Theory calculations. It is found that Ptc on PdAu (Ptc-PA) with reasonable atomic strain upshifts the d-band center and exposes high potential surface, indicating the sufficient active sites to achieve superior biocatalytic performances. Besides, the Pd shell and Au core serve as storage layers providing abundant energetic charge carriers. The Ptc-PA exhibits a prominent peroxidase (POD)-like activity with the catalytic efficiency (K cat/K m) of 1.50 × 109 mM−1 min−1, about four orders of magnitude higher than natural horseradish peroxidase (HRP), while catalase (CAT)-like and superoxide dismutase (SOD)-like activities of Ptc-PA are also comparable to those of natural enzymes. Biological experiments demonstrate that the detection limit of the Ptc-PA-based catalytic detection system exceeds that of visual inspection by 132-fold in clinical cancer diagnosis. Besides, Ptc-PA can reduce multi-organ acute inflammatory damage and mitigate oxidative stress disorder.

Abstract Invasive pneumococcal disease (IPD) due to non-vaccine serotypes after the introduction of pneumococcal conjugate vaccines (PCV) remains a global concern. This study used pathogen genomics to evaluate changes in invasive pneumococcal lineages before, during and after vaccine introduction in South Africa. We included genomes (N = 3104) of IPD isolates from individuals aged

Abstract Tibetan Buddhist monasteries constitute significant cultural heritages of ethnic minorities, evolving into the Principal-Subordinate Monastery System (PSMS) with profound historical and cultural significance. This system exhibits an integrated hierarchical structure in terms of religious dominance, political administration, and cultural diffusion. Existing research primarily focuses on internal humanistic factors such as governance patterns, while there is not any research focused on its patterns and manifestations in spatial distribution. This study aims to elucidate the spatial distribution characteristics of the PSMS in Hehuang region, including the Tibetan Buddhist monasteries from all sects in the Hehuang region since the Song Dynasty It establishes a hierarchical PSMS database based on the affiliation relationships, aimed at storing spatial and property information related to PSMS. The database standardizes the naming and coding of monasteries, and classifies them through hierarchical relationships to ensure data consistency and usability. Finally, the classified and coded monastery data were analyzed by GIS tools to form the PSMS spatial distribution characterisation framework. Results reveal that (1) Monasteries demonstrate notable spatial clustering patterns from both holistic and sectarian perspectives, with density being influenced by the principal monastery’s position. (2) Almost every PSMS exhibits a spatial pattern centered around the principal monastery, with subordinate monasteries clustering within a defined range correlated with the administrative region of the principal monastery. (3) PSMS scale variations are controlled by principal monasteries, exhibiting positive correlations in hierarchical structure, control quantity, and distribution range. (4) The spatial orientation of PSMS correlates with river distribution, while the relationships among mountain ranges require further investigation. These findings provide initial insights into the spatial distribution characteristics of PSMS, confirming the spatial influence of the principal monastery. Besides, this study established an innovative spatial research framework for heritage clusters with multiple types and hierarchies. Thus, this study offers new insights into the spatial distribution of Tibetan Buddhist monastery heritage and presents a framework for further examining the spatial distribution of the Tibetan Buddhist monastery heritage in other regions, as well as other heritage clusters where connected and clustered through religious and cultural ties.

Abstract δ-MnO2 is an important component of environmental minerals and is among the strongest sorbents and oxidants. The crystalline morphology of δ-MnO2 is one of the key factors affecting its reactivity. In this work, δ-MnO2 was initially synthesized and placed in an acidic environment to react with Mn2+ and undergo a crystalline transformation. During the transformation of crystalline δ-MnO2, kinetic sampling was conducted, followed by analyses of the structures and morphologies of the samples. The results showed that at pH 2.5 and 4, δ-MnO2 nanoflakes spontaneously self-assembled into nanoribbons via edge-to-edge assembly in the initial stage. Subsequently, these nanoribbons attached to each other to form primary nanorods through a face-to-face assembly along the c-axis. These primary nanorods then assembled along the (001) planes and lateral surfaces, achieving further growth and thickening. Since a lower pH is more favorable for the formation of vacancies in δ-MnO2, δ-MnO2 can rapidly adsorb Mn2+ directly onto the vacancies to form tunnel walls. At the same time, the rapid formation of the tunnel walls leads to a quick establishment of hydrogen bonding between adjacent nanoribbons, enabling the assembly of these nanoribbons into primary nanorods. Therefore, in a solution with the same concentration of Mn2+, the structure transformation and morphology evolution of δ-MnO2 to α-MnO2 occur faster at pH 2.5 than at pH 4. These findings provide insights into the mechanism for crystal growth from layer-based to tunnel-based nanorods and methods for efficient and controlled syntheses of nanomaterials.

Abstract Background Anaplastic lymphoma kinase (ALK) test in advanced non‐small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real‐world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC. Methods In this real‐world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)‐VENTANA‐D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well. Results The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC‐VENTANA‐D5F3 revealed an intra‐hospital consistency rate of 98.2% (879/895) and an inter‐hospital consistency rate of 99.2% (646/651). IHC‐VENTANA‐D5F3 was used in 53.6%, real‐time polymerase chain reaction (RT‐PCR) in 25.4%, next‐generation sequencing (NGS) in 18.3%, and fluorescence in‐situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC‐VENTANA‐D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT‐PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05). Conclusions This study highlights the real‐world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC‐VENTANA‐D5F3 with high consistency and distinct clinicopathological features in ALK‐positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision‐making in NSCLC.

Pulmonary mixed squamous cell and glandular papilloma (MSCGP) is a subtype of pulmonary papilloma, which can be classified as central type and peripheral type based on its site of development. The central type is the most common. The clinical manifestations of pulmonary MSCGP are mainly related to the location of the tumor. Surgery is the main treatment for this disease. Bronchoscopic interventional treatment for the MSCGP in the central trachea could receive satisfactory effect. We reported a patient suffered from diffuse tracheal MSCGP who was treated by bronchoscopic interventional treatment in Respiratory Disease Center, Dongzhimen Hospital of Beijing University of Chinese Medicine, aiming to enhance the recognition of the clinical features and provide clinical references for the diagnosis and treatment of such disease.