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Abstract Background Recent advances in ultrasound technology have led to widespread adoption of ultrasonic energy devices in liver resections. While various studies have assessed the comparative advantages of ultrasonic devices and traditional clamp-crushing, their findings vary. Moreover, a specific systematic review on this topic has not yet been conducted. Objectives This study aims to present a comprehensive, up-to-date analysis comparing outcomes between ultrasonic devices and conventional clamp-crushing methods in liver resection, based on currently available literature. Patients and methods We conducted a systematic literature search in databases such as PubMed, Embase, Web of Science, and CNKI up to November 2023. Studies that compared the efficacy or safety of ultrasonic devices against traditional clamp-crushing methods in hepatectomy were included. The analysis covered intraoperative outcomes like operating time, blood loss, and transfusion rate, as well as postoperative outcomes such as complication rate, mortality, postoperative bleeding, and bile leakage. Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK) and Stata 17.0 (Stata Corp, College Station, TX, USA) were used for data analysis. Results Thirteen studies, involving a total of 1,417 patients (630 using ultrasonic devices and 787 using clamp-crushing methods), were included. The clamp-crush method resulted in a shorter operation time. Contrarily, the ultrasonic device group experienced reduced blood loss and lower transfusion rates. Postoperatively, there was no significant difference in mortality or postoperative bleeding between the groups. However, the ultrasonic group had a lower overall complication rate, particularly a reduced incidence of bile leakage. Overall, the ultrasonic devices were associated with improved perioperative outcomes. Conclusions The findings suggest that ultrasonic devices provide better outcomes in hepatectomy compared to traditional clamp-crushing techniques. Nonetheless, large-scale randomized controlled trials are needed to confirm these results due to potential heterogeneity and biases. The choice of using ultrasonic devices should consider the surgeon’s experience and individual patient circumstances.

Abstract Supercoiled flagellar filaments function as mechanical propellers within the bacterial flagellum complex, playing a crucial role in motility. Flagellin, the building block of the filament, features a conserved inner D0/D1 core domain across different bacterial species. In contrast, approximately half of the flagellins possess additional, highly divergent outer domain(s), suggesting varied functional potential. In this study, we report atomic structures of flagellar filaments from three distinct bacterial species: Cupriavidus gilardii, Stenotrophomonas maltophilia, and Geovibrio thiophilus. Our findings reveal that the flagella from the facultative anaerobic G. thiophilus possesses a significantly more negatively charged surface, potentially enabling adhesion to positively charged minerals. Furthermore, we analyze all AlphaFold predicted structures for annotated bacterial flagellins, categorizing the flagellin outer domains into 682 structural clusters. This classification provides insights into the prevalence and experimental verification of these outer domains. Remarkably, two of the flagellar structures reported herein belong to a distinct cluster, indicating additional opportunities on the study of the functional diversity of flagellar outer domains. Our findings underscore the complexity of bacterial flagellins and open up possibilities for future studies into their varied roles beyond motility.

The performance of a solid oxide fuel cell (SOFC) is strongly associated with the activity and durability of the cathode, where the oxygen reduction reaction occurs. In this study, we report our findings in the development of an Nb-doped PrBa0.8Ca0.2Co2O6−δ (PrBa0.8Ca0.2Co2−xNbxO6−δ, x = 0, 0.025, 0.05, and 0.1, denoted as PBCCNx) perovskite composite as the SOFC cathode. Analyses of X-ray diffraction (XRD) patterns and energy-dispersive transmission electron microscopy (TEM-EDS) images suggest that after being treated at 950 °C in air, PBCCN0.05 mainly contains phases of Ca- and Nb-doped PrBaCo2O6−δ double perovskite, PrCoO3 perovskite with Ca and Nb doping, and Ba3Ca1.18Nb1.82O9−δ. When evaluated as an SOFC cathode, the PBCCN0.05 mixture has shown a low polarization resistance of 0.0074 Ω∙cm2 at 800 °C in La0.8Sr0.2Ga0.8Mg0.2O3 electrolyte symmetrical cells. Accordingly, anode-supported single cells with a configuration of Ni–Zr0.84Y0.16O2−δ (YSZ)/YSZ/Gd0.1Ce0.9O2−δ/PBCCN0.05 display high electrochemical performance, with a peak power density of 1.81 W∙cm−2 and a reasonable durability of 100 h at 800 °C. PBCCN0.05 possesses a higher concentration of oxygen vacancies, a faster oxygen surface adsorption‒dissociation rate, and an increased mass ratio of PrCoO3 perovskite with Ca and Nb doping compared to PrBa0.8Ca0.2Co2O6−δ without Nb doping.

Abstract Background Lifestyle intervention is the first-line treatment for PCOS. Numerous studies have investigated the effect of various lifestyle factors, including dietary habit, smoking, and alcohol consumption on PCOS women. These studies have found that such factors may be associated with physiological parameters such as androgen, and emotional states like anxiety or depression. Smoking, a harmful lifestyle habit widely recognized to contribute to various diseases, has also been found to be related to PCOS. Current research has not adequately compared the effects of smoking with other lifestyle habits on PCOS, and there is little mention of its relationship with the emotional states of patients with PCOS. To further elucidate the association between smoking and other lifestyle factors with clinical symptoms in patients with PCOS, we conducted a cross-sectional evaluation using data from Peking University Third Hospital, with a special focus on analyzing smoking habits and comparing it with a variety of lifestyle factors. Methods This cross-sectional study included 601 PCOS women and 184 healthy controls who underwent physical examinations, hormone profiles and psychological measures. We assessed the association between smoking and the clinical symptoms in PCOS women. Results We found a significant correlation between smoking and the degree of depression in PCOS women among the three emotional states: anxiety, depression, and stress. Smoking was also significantly associated with testosterone level in PCOS participants, suggesting that PCOS women who smoke exhibited more severe depressive symptoms and higher testosterone level. In addition, compared to the control group, PCOS women had notably higher testosterone (T) and luteinizing hormone (LH) levels. Smoke and alcohol were statistically significantly more common in women with PCOS than the Control. Conclusion Women with PCOS who smoke were found to have elevated testosterone levels and more severe depression. These findings suggest that clinicians should monitor smoking women with PCOS for symptoms of depression and assess their hyperandrogenic status.

Abstract PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (

Abstract Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

Background Advances in blood biomarker discovery have enabled the improved diagnosis and prognosis of Alzheimer's disease (AD). Most branched-chain amino acids, except isoleucine (Ile), are correlated with both mild cognitive impairment (MCI) and AD. Therefore, this study investigated the association between serum Ile levels and MCI/AD. Methods This study stratified 700 participants from the Alzheimer's Disease Neuroimaging Initiative database into four diagnostic groups: cognitively normal, stable MCI, progressive MCI, and AD. Analysis of covariance and chi-square analyses were used to test the demographic data. Receiver operating curve analyses were used to calculate the diagnostic accuracy of different biomarkers and were compared by MedCalc 20. Additionally, Cox proportional hazards models were used to measure the ability of serum Ile levels to predict disease conversion. Finally, a linear mixed-effects model was used to evaluate the associations between serum Ile levels and cognition, brain structure, and metabolism. Results Serum Ile concentration was decreased in AD and demonstrated significant diagnostic efficacy. The combination of serum Ile and cerebrospinal fluid (CSF) phosphorylated tau (P-tau) improved the diagnostic accuracy in AD compared to total tau (T-tau) alone. Serum Ile levels significantly predicted the conversion from MCI to AD (cutoff value of 78.3 μM). Finally, the results of this study also revealed a correlation between serum Ile levels and the Alzheimer's Disease Assessment Scale cognitive subscale Q4. Conclusions Serum Ile may be a potential biomarker of AD. Ile had independent diagnostic efficacy and significantly improved the diagnostic accuracy of CSF P-tau in AD. MCI patients with a lower serum Ile level had a higher risk of progression to AD and a worse cognition assessment.

Abstract Background and Objective Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. Methods Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. Results Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (T max) of 1.0–4.0 h post-dose and a long terminal half-life (t ½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration–time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. Conclusions Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. Registration ChinadrugTrials.org.cn identifier: CTR20212852.

Abstract The mismatch between solar radiation resources and building heating demand on a seasonal scale makes cross-seasonal heat storage a crucial technology, especially for plateau areas. Utilizing phase change materials with high energy density and stable heat output effectively improves energy storage efficiency. This study integrates cascaded phase change with a cross-seasonal heat storage system aimed at achieving low-carbon heating. The simulation analyzes heat distribution and temperature changes from the heat storage system to the heating terminal. The results indicate that although the solar collectors operate for 26.3% of the total heat storage and heating period, the cumulative heat stored is 45.4% higher than the total heating load. Heat transferred by the cross-seasonal heat storage system accounts for up to 61.2% of the total heating load. Therefore, the system reduces fuel consumption by 77.6% compared to conventional fossil fuel heating systems. Moreover, radiant floor heating terminals, with a wide range of operating temperatures, match well with cascaded phase change heat storage and can reduce operation time by 19.5% and heat demand by 5.2% compared to conventional radiators. In addition to demonstrating the feasibility of applying cascaded phase change technology in cross-seasonal heat storage heating, this study reveals the lifecycle sustainability due to the shortened heat storage period. The configuration, parameters, and simulation results provide a reference basis for system application and design.

Objective: Investigate the effects of Lonicera caerulea anthocyanin complex liquid preparation (compound made of Lonicera caerulea L., Polygonatum sibiricum, Inonotus obliquus, LPI) on glucose and lipid metabolism in type 2 diabetes mellitus (T2D) mice. Methods: T2D model in mice was constructed by high-fat feeding combined with streptozotocin. The mice were randomly divided into 6 groups: Blank control group, diabetes model group, low, middle and high dose sample group and metformin positive control group. After continuous intervention for 28 days, the body mass data and physiological and biochemical indexes of mice were measured and recorded, and the pathological observation of the organs of mice was performed. Results: Each dose group of LPI could increase the weight of T2D mice, improve the symptoms of organ injury, significantly reduce serum insulin level (P

Understanding the influence mechanism of microstructures and inclusions during heat treatment on the corrosion resistance of L-PBF 316L stainless steel (SS) is crucial for steel quality control and subsequent industrial application. In this study, the evolution of microstructure, inclusions and passive film in the L-PBF 316L SS during heat treatment at the temperature of 1000 °C and 1200 °C for 2 h, including crystal characteristics, dislocation density, passivation film composition and so on, were characterized by electron backscatter diffraction (EBSD), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). The corrosion resistance of L-PBF 316L SS samples was evaluated by Tafel test and electrochemical impedance spectroscopy test. The corrosion mechanisms of L-PBF 316L SS before and after heat treatment were clarified to elucidate the intrinsic effect of microstructure and inclusions on the corrosion resistance of the steel. Results showed that the heat treatment conducted at 1200 °C effectively reduced the number of grain boundaries and induced a substantial number of Σ3 twin grain boundaries in the L-PBF 316L SS, thereby efficiently impeding the precipitation of detrimental phases and reducing corrosion susceptibility at the grain boundaries. Meanwhile, the recrystallization-induced rearrangement of dislocations and the homogenization of grains effectively facilitated the growth of passivation film, thereby increasing the corrosion resistance of HT1200 sample. Additionally, the increase of MoO3 content compensated for the detrimental impact on the stability of the passivation film resulting from the reduction in chromium oxide content. Transformation from the MnO–SiO2–Cr2O3 inclusions in the as-built sample to the SiO2 inclusions in the HT1200 sample would also retard the penetration of corrosive ions into the steel matrix.

Pores are among the primary defects in 316L stainless steel when fabricated through laser powder bed fusion (L-PBF). To better understand and precisely control the formation behavior of pores in the L-PBF-manufactured 316L stainless steel, effects of L-PBF process parameters on the melt pool and pore characteristics have been investigated. A method utilized for extreme values statistics analysis was also applied to investigate and predict the sizes of pores. Relationships among the count of measurements, the laser energy density, the reduced variate, and the maximum pore size were revealed. The findings showed an overall increase in melt pool depth as the laser energy densities was raised, yet the magnitude of this growth weakened as the laser energy density continued to increase. Conversely, it was discovered that the connection between the width of the melt pool and the density of laser energy exhibited a markedly less distinct correlation. As laser energy density escalated, there was a shift in the melt pool mode from conduction-based to a transitional phase, and upon further elevation of the laser energy density, it transitioned to keyhole mode. To obtain a reliable statistical analysis of pores, at least 40 measurements should be acquired for the estimation of the pore sizes by taking comprehensive consideration of time cost. Beside, in all three melt pool modes, at a fixed observation area, the maximum size of pores generally decreased with the escalation in laser energy densities.

In gestational diabetes mellitus (GDM), adipose tissue undergoes metabolic disturbances and chronic low-grade inflammation. Alternative polyadenylation (APA) is a post-transcriptional modification mechanism that generates mRNA with variable lengths of 3' untranslated regions (3'UTR), and it is associated with inflammation and metabolism. However, the role of APA in GDM adipose tissue has not been well characterized. In this study, we conducted transcriptomic and proteomic sequencing on subcutaneous and omental adipose tissues from both control and GDM patients. Using Dapars, a novel APA quantitative algorithm, we delineated the APA landscape of adipose tissue, revealing significant 3'UTR elongation of mRNAs in the GDM group. Omental adipose tissue exhibited a significant correlation between elongated 3'UTRs and reduced translation levels of genes related to metabolism and inflammation. Validation experiments in THP-1 derived macrophages (TDMs) demonstrated the impact of APA on translation levels by overexpressing long and short 3'UTR isoforms of a representative gene LRRC25. Additionally, LRRC25 was validated to suppress proinflammatory polarization in TDMs. Further exploration revealed two underexpressed APA trans-acting factors, CSTF3 and PPP1CB, in GDM omental adipose tissue. In conclusion, this study provides preliminary insights into the APA landscape of GDM adipose tissue. Reduced APA regulation in GDM omental adipose tissue may contribute to metabolic disorders and inflammation by downregulating gene translation levels. These findings advance our understanding of the molecular mechanisms underlying GDM-associated adipose tissue changes.

Abstract Background Glucose metabolic disorder is associated with the risk of heart failure (HF). Adiposity is a comorbidity that is inextricably linked with abnormal glucose metabolism in older individuals. However, the effect of adiposity on the association between glucose metabolic disorder and HF risk, and the underlying mechanism remain unclear. Methods A total of 13,251 participants aged ≥ 60 years from a cohort study were categorized into euglycemia, prediabetes, uncontrolled diabetes, and well-controlled diabetes. Adiposity was assessed using body mass index (BMI), waist-to-hip ratio (WHR), and visceral fat area (VFA). Adiposity-associated metabolic activities were evaluated using adiponectin-to-leptin ratio (ALR), homeostatic model assessment of insulin resistance (HOMA-IR), and triglyceride-glucose index (TyG). The first occurrence of HF served as the outcome during the follow-up period. Results A total of 1,138 participants developed HF over the course of an average follow-up period of 10.9 years. The rate of incident HF occurrence was higher in prediabetes, uncontrolled diabetes, and well-controlled diabetes participants compared to that in euglycemia participants. However, the high rates were significantly attenuated by BMI, VFA, and WHR. For WHR in particular, the hazard ratio for incident HF was 1.18 (95% confidence interval (CI): 1.03, 1.35, P adj. =0.017) in prediabetes, 1.59 (95% CI: 1.34, 1.90, P adj.

Abstract Background Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear. Results Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3′-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain‐of‐function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A. Conclusions These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.

Abstract Most of the existing methods for harmonic analysis are from frequency‐domain perspective. In fact, the essential factor for generating harmonics is non‐linear characteristic or time‐varying property. Therefore, the harmonic generation mechanism and the harmonic source location method are investigated from the time domain perspective in this paper. Firstly, a general model of non‐harmonic sources is established. The non‐harmonic sources will match well with the proposed general model while the harmonic source will not. Then correlation coefficient that reflects compliance degree between each device and the general model is defined for distinguishing harmonic sources from non‐harmonic sources. On this basis, a novel time‐domain harmonic source location method is proposed. Numerous simulations and experiments have demonstrated that the proposed method has good performance under fluctuations, saturations, pre‐distortions, transient process, and resonances. The defined correlation coefficient can reflect non‐linearity/time‐varying degree of the harmonic source, which can be used for evaluating harmonic emission level of each harmonic source. On this basis, a simple harmonic responsibility division method is proposed, which is immune to possible fluctuations, pre‐distortions, saturations, resonances, and impedance variation.

Abstract Vermicomposting utilizes the synergistic effect of earthworms with microorganisms to accelerate the stabilization of organic matter in biowastes. Nevertheless, the exact mechanism behind the maturity of vermicompost and the growth of earthworms exposed to biochar of varying particle sizes remains unclear. This study presents an investigation of the effect of biochar particle size on earthworm (Eisenia fetida) survival, microbial diversity, and the quality of vermicompost products. To address these issues, pelletized dewatered sludge samples from a municipal sewage treatment plant were amended with pine-based biochar with particle sizes of 1–2 mm, 25–75 μm, 200 nm, and 60 nm as the substrate for vermicomposting. This study revealed that the addition of millimeter-scale biochar and micron-scale biochar significantly promoted the degradation of organic matter since the organic matter in the treatment with 1–2 mm biochar at the end of the vermicomposting experiment decreased by 12.6%, which was equivalent to a 1.9-fold increase compared with that of the control. Excessive nanopowdering of nanobiochar significantly affected the survival of earthworms and led to 24.4–33.3% cumulative mortality, while millimeter-scale (mm) biochar and micron-scale (μm) biochar achieved zero mortality. The findings of this study could be used for evaluating the potential impact of nanoscale biochar to earthworms and guiding biochar-augmented vermicomposting. Graphical Abstract

Abstract Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Abstract Background In the field of ornamental horticulture, phenotypic mutations, particularly in leaf color, are of great interest due to their potential in developing new plant varieties. The introduction of variegated leaf traits in plants like Heliopsis helianthoides, a perennial herbaceous species with ecological adaptability, provides a rich resource for molecular breeding and research on pigment metabolism and photosynthesis. We aimed to explore the mechanism of leaf variegation of Heliopsis helianthoides (using HY2021F1-0915 variegated mutant named HY, and green-leaf control check named CK in 2020 April, May and June) by analyzing the transcriptome and metabolome. Results Leaf color and physiological parameters were found to be significantly different between HY and CK types. Chlorophyll content of HY was lower than that of CK samples. Combined with the result of Weighted Gene Co-expression Network Analysis (WGCNA), 26 consistently downregulated differentially expressed genes (DEGs) were screened in HY compared to CK subtypes. Among the DEGs, 9 genes were verified to be downregulated in HY than CK by qRT-PCR. The reduction of chlorophyll content in HY might be due to the downregulation of FSD2. Low expression level of PFE2, annotated as ferritin-4, might also contribute to the interveinal chlorosis of HY. Based on metabolome data, differential metabolites (DEMs) between HY and CK samples were significantly enriched on ABC transporters in three months. By integrating DEGs and DEMs, they were enriched on carotenoids pathway. Downregulation of four carotenoid pigments might be one of the reasons for HY’s light color. Conclusion FSD2 and PFE2 (ferritin-4) were identified as key genes which likely contribute to the reduced chlorophyll content and interveinal chlorosis observed in HY. The differential metabolites were significantly enriched in ABC transporters. Carotenoid biosynthesis pathway was highlighted with decreased pigments in HY individuals. These findings not only enhance our understanding of leaf variegation mechanisms but also offer valuable insights for future plant breeding strategies aimed at preserving and enhancing variegated-leaf traits in ornamental plants.

An improved method was developed for the detection of 16 polycyclic aromatic hydrocarbons (PAHs) in mainstream cigarette smoke during combustion. The methodological approach involved matrix matching standard solution preparation, direct injection of the extraction solution, and measurement of standard linearity curves to quantitatively analyze the release of target compounds. Considering the diverse physical and chemical properties as well as distribution patterns of the 16 PAHs in cigarette smoke, the impact of room temperature and high-temperature ion sources on the response of target compounds was investigated. Additionally, the preparation methods of matrix solvents and the matrix effects on the quantitative results of target compounds were also explored. Furthermore, a systematic study was conducted on the smoke release distribution of commercially available cigarettes with different circumferences. The results demonstrated that direct injection of sample extract eliminates the need for sample purification, concentration, and other processing steps employed in current detection methods. This simplifies sample pretreatment procedures while reducing organic solvent usage and consumables consumption. Moreover, it resolves issues related to low operational efficiency when dealing with large quantities of samples. The use of matrix solvent to prepare standard solution effectively reduces the influence of matrix effect, and solves the technical problem of low recovery of target substance in flue gas caused by no purification treatment when using gas chromatography-tandem mass spectrometry (GC-MS/MS) to analyze 16 kinds of PAHs. Under the normal working parameters of the instrument, the electron impact ion source (EI) was used under high temperature to improve the ionization efficiency of the targets in complex matrix and to ensure the accurate analysis of targets with low concentrations. The correlation coefficients (R2) of the calibration curves for 16 PAHs are 0.996 4-0.999 8, the limits of dectection and the limits of quantification are 0.29-1.48, 0.95-4.94 ng/cigarette, respectively. Under different concentration levels, the average recovery is 87.71%-123.26%, and the precision is within 1.58%-9.45%. By analyzing the reference cigarette 3R4F, there is no significant difference between this method and those reported in the literature. The total amount of PAHs released from 58 brands of cigarette samples are 742.76-1 505.99 ng/cigarette. At the same time, with the decrease of tar content in cigarette, the release of PAHs will be reduced accordingly. This method is simple, practical, stable, and accurate, providing more technical means for the detection of trace PAHs in cigarette smoke.

Abstract The recent upswing in the integration of spatial multi-omics for conducting multidimensional information measurements is opening a new chapter in biological research. Mapping the landscape of various biomolecules including metabolites, proteins, nucleic acids, etc., and even deciphering their functional interactions and pathways is believed to provide a more holistic and nuanced exploration of the molecular intricacies within living systems. Mass spectrometry imaging (MSI) stands as a forefront technique for spatially mapping the metabolome, lipidome, and proteome within diverse tissue and cell samples. In this review, we offer a systematic survey delineating different MSI techniques for spatially resolved multi-omics analysis, elucidating their principles, capabilities, and limitations. Particularly, we focus on the advancements in methodologies aimed at augmenting the molecular sensitivity and specificity of MSI; and depict the burgeoning integration of MSI-based spatial metabolomics, lipidomics, and proteomics, encompassing the synergy with other imaging modalities. Furthermore, we offer speculative insights into the potential trajectory of MSI technology in the future.

Abstract C-X-C motif chemokine receptor 4 (CXCR4) is a promising therapeutic target of breast cancer because it is overexpressed on cell surface of all molecular subtypes of breast cancer including triplenegative breast cancer (TNBC). Herein, CXCR4 antagonistic peptide-NaGdF4 nanodot conjugates (termed as anti-CXCR4-NaGdF4 NDs) have been constructed for magnetic resonance imaging (MRI)-guided biotherapy of TNBC through conjugation of the C-X-C Motif Chemokine 12 (CXCL12)-derived cyclic peptide with tryptone coated NaGdF4 nanodots (5 ± 0.5 nm in diameter, termed as Try-NaGdF4 NDs). The as-prepared anti-CXCR4-NaGdF4 NDs exhibits high longitudinal relaxivity (r 1) value (21.87 mM−1S−1), reasonable biocompatibility and good tumor accumulation ability. The features of anti-CXCR4-NaGdF4 NDs improve the tumor-MRI sensitivity and facilitate tumor biotherapy after injection in mouse-bearing MDA-MB-231 tumor model in vivo. MRI-guided biotherapy using anti-CXCR4-NaGdF4 NDs enables to suppress 46% tumor growth. In addition, about 47% injection dose of anti-CXCR4-NaGdF4 NDs is found in the mouse urine at 24 h post-injection. These findings demonstrate that anti-CXCR4-NaGdF4 NDs enable to be used as renal clearable nanomedicine for biotherapy and MRI of breast cancer.

Abstract IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

Abstract Salt deposits are indicative of relatively extreme climate events. However, due to insufficient independent temperature proxies, paleotemperature records obtained from salt deposition are still lack. The Paleocene evaporite sequence deposited in the Hongze Depression of Subei Basin of eastern China provides an important terrestrial sediment record during this period. In this study we present total of 488 homogenization temperature (Th) data of halite fluid inclusions from drilling core with different stratigraphic depth after detailed petrological observation. The obtained Th ranged from 17.7 °C to 52.3 °C, with the mean Th value of 34.1 °C that in good agreement with the previous studies of climatic proxies. Our study shows that primary fluid inclusions of halite can serve as a robust tool to construct the ancient earth surface temperature.

Abstract Background The utilization of a double trigger, involving the co-administration of gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) for final oocyte maturation, is emerging as a novel approach in gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during controlled ovarian hyperstimulation (COH). This protocol involves administering GnRH-a and hCG 40 and 34 h prior to ovum pick-up (OPU), respectively. This treatment modality has been implemented in patients with low/poor oocytes yield. This study aimed to determine whether the double trigger could improve the number of top-quality embryos (TQEs) in patients with fewer than three TQEs. Methods The stimulation characteristics of 35 in vitro fertilization (IVF) cycles were analyzed. These cycles were triggered by the combination of hCG and GnRHa (double trigger cycles) and compared to the same patients’ previous IVF attempt, which utilized the hCG trigger (hCG trigger control cycles). The analysis involved cases who were admitted to our reproductive center between January 2018 and December 2022. In the hCG trigger control cycles, all 35 patients had fewer than three TQEs. Results Patients who received the double trigger cycles yielded a significantly higher number of 2PN cleavage embryos (3.54 ± 3.37 vs. 2.11 ± 2.15, P = 0.025), TQEs ( 2.23 ± 2.05 vs. 0.89 ± 0.99, P

Abstract In traditional von Neumann computing architecture, the efficiency of the system is often hindered by the data transmission bottleneck between the processor and memory. A prevalent approach to mitigate this limitation is the use of non-volatile memory for in-memory computing, with spin–orbit torque (SOT) magnetic random-access memory (MRAM) being a leading area of research. In this study, we numerically demonstrate that a precise combination of damping-like and field-like spin–orbit torques can facilitate precessional magnetization switching. This mechanism enables the binary memristivity of magnetic tunnel junctions (MTJs) through the modulation of the amplitude and width of input current pulses. Building on this foundation, we have developed a scheme for a reconfigurable spintronic logic gate capable of directly implementing Boolean functions such as AND, OR, and XOR. This work is anticipated to leverage the sub-nanosecond dynamics of SOT-MRAM cells, potentially catalyzing further experimental developments in spintronic devices for in-memory computing.

Abstract The fault diagnosis of cargo UAVs (Unmanned Aerial Vehicles) is crucial to ensure the safety of logistics distribution. In the context of smart logistics, the new trend of utilizing knowledge graph (KG) for fault diagnosis is gradually emerging, bringing new opportunities to improve the efficiency and accuracy of fault diagnosis in the era of Industry 4.0. The operating environment of cargo UAVs is complex, and their faults are typically closely related to it. However, the available data only considers faults and maintenance data, making it difficult to diagnose faults accurately. Moreover, the existing KG suffers from the problem of confusing entity boundaries during the extraction process, which leads to lower extraction efficiency. Therefore, a fault diagnosis knowledge graph (FDKG) for cargo UAVs constructed based on multi-domain fusion and incorporating an attention mechanism is proposed. Firstly, the multi-domain ontology modeling is realized based on the multi-domain fault diagnosis concept analysis expression model and multi-dimensional similarity calculation method for cargo UAVs. Secondly, a multi-head attention mechanism is added to the BERT-BILSTM-CRF network model for entity extraction, relationship extraction is performed through ERNIE, and the extracted triples are stored in the Neo4j graph database. Finally, the DJI cargo UAV failure is taken as an example for validation, and the results show that the new model based on multi-domain fusion data is better than the traditional model, and the precision rate, recall rate, and F1 value can reach 87.52%, 90.47%, and 88.97%, respectively.

Abstract Background Lung cancer, with high morbidity and mortality, is the commonest respiratory system neoplasm, which seriously endangers the life safety of patients. In this study, the effect of PRPS2 on cell progression was preliminarily investigated. Methods Immunohistochemical staining, western blot and reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) were performed to verify the expression level of PRPS2 in lung cancer. Lung cancer cell lines with stable downregulation of PRPS2 were constructed in A549 cells and NCIH460 cells. The function of PRPS2 silencing on the proliferation ability was verified by the EdU and cell colony formation experiment. Scratch and transwell tests were conducted to verify the role of PRPS2 silencing on the migratory and invasive ability of cells. The impact of PRPS2 silencing on cell apoptosis and cell cycle was verified by flow cytometry test. The effects of PRPS2 silencing on apoptosis‐associated proteins were assessed by western blot assay. The function of PRPS2 silencing on tumor growth in vivo was studied through xenograft tumor experiment. Results In comparison with normal tissues, PRPS2 was upregulated in lung cancer tissues. PRPS2 knockdown notably hindered the migratory ability, invasive ability and proliferation, but accelerated cell apoptosis. In vivo experiments confirmed that PRPS2 silencing blocked the growth of transplanted tumors. Conclusion In lung cancer, PRPS2 silencing suppressed the malignant progression, indicating that PRPS2 might be a novel biomarker for lung cancer treatment and diagnosis.

Abstract A novel method based on machine learning is proposed to estimate the electromagnetic radiation level at the ground plane near fifth‐generation (5G) base stations. The machine learning model was trained using data from various 5G base stations, enabling it to estimate the electric field intensity at any arbitrary radiation point when the base station provides service to different numbers of 5G terminals which are in different service modes. The inputs required for the model include the transmit power of the antenna, the antenna gain, the distance between the 5G base station and 5G terminals, terminal service modes, the number of 5G terminals and the environmental complexity around the 5G base station. Experimental results demonstrate the feasibility and effectiveness of the estimation method, with the mean absolute percentage error of the machine learning model being approximately 5.98%. This level of accuracy showcases the reliability of the approach. Moreover, the proposed method offers low costs when compared with on‐site measurements. The estimated results can be utilised to reduce test costs and provide valuable guidance for optimal site selection, thereby facilitating radio wave coverage or electromagnetic radiation regulation of 5G base stations.

Based on the latest results of near-source exploration in the Middle and Lower Jurassic of the Tuha Basin, a new understanding of the source rocks, reservoir conditions, and source-reservoir-cap rock combinations of the Jurassic Shuixigou Group in the Taibei Sag is established using the concept of the whole petroleum system, and the coal-measure whole petroleum system is analyzed thoroughly. The results are obtained in three aspects. First, the coal-measure source rocks of the Badaowan Formation and Xishanyao Formation and the argillaceous source rocks of the Sangonghe Formation in the Shuixigou Group exhibit the characteristics of long-term hydrocarbon generation, multiple hydrocarbon generation peaks, and simultaneous oil and gas generation, providing sufficient oil and gas sources for the whole petroleum system in the Jurassic coal-bearing basin. Second, multi-phase shallow braided river delta–shallow lacustrine deposits contribute multiple types of reservoirs, e.g. sandstone, tight sandstone, shale and coal rock, in slope and depression areas, providing effective storage space for the petroleum reservoir formation in coal-measure strata. Third, three phases of hydrocarbon charging and structural evolution, as well as effective configuration of multiple types of reservoirs, result in the sequential accumulation of conventional-unconventional hydrocarbons. From high structural positions to depression, there are conventional structural and structural-lithological reservoirs far from the source, low-saturation structural-lithological reservoirs near the source, and tight sandstone gas, coal rock gas and shale oil accumulations within the source. Typically, the tight sandstone gas and coal rock gas are the key options for further exploration, and the shale oil and gas in the depression area is worth of more attention. The new understanding of the whole petroleum system in the coal measures could further enrich and improve the geological theory of the whole petroleum system, and provide new ideas for the overall exploration of oil and gas resources in the Tuha Basin.

Abstract FeSe is one of the most enigmatic superconductors. Among the family of iron-based compounds, it has the simplest chemical makeup and structure, and yet it displays superconducting transition temperature ( T c $T_{\text{c}}$ ) spanning 0 to 15 K for thin films, while it is typically 8 K for single crystals. This large variation of T c $T_{\text{c}}$ within one family underscores a key challenge associated with understanding superconductivity in iron chalcogenides. Here, using a dual-beam pulsed laser deposition (PLD) approach, we have fabricated a unique lattice-constant gradient thin film of FeSe which has revealed a clear relationship between the atomic structure and the superconducting transition temperature for the first time. The dual-beam PLD that generates laser fluence gradient inside the plasma plume has resulted in a continuous variation in distribution of edge dislocations within a single film, and a precise correlation between the lattice constant and T c $T_{\text{c}}$ has been observed here, namely, T c ∝ c − c 0 $T_{\text{c}} \propto \sqrt{c- c_{0}}$ , where c is the c-axis lattice constant (and c 0 $c_{0}$ is a constant). This explicit relation in conjunction with a theoretical investigation indicates that it is the shifting of the d xy $d_{\text{xy}}$ orbital of Fe which plays a governing role in the interplay between nematicity and superconductivity in FeSe.

Abstract Objective This cross‐sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID‐19 in China. Methods This study was conducted by 45 tertiary Grade‐A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID‐19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self‐reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions The incidence of dysosmia and dysgeusia following infection with the SARS‐CoV‐2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS‐CoV‐2 vaccination, history of head‐facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.

Bacterial communities play a crucial role in maintaining the stability of river ecosystems and driving biogeochemical cycling, exhibiting high sensitivity to environmental change. However, understanding the spatial scale effects and assembly mechanisms of riverine bacterial communities under distinct anthropogenic disturbances remains a challenge. Here, we investigated bacterial communities across three distinct watersheds [i.e., intensive urban (UW), intensive agricultural (AW), and natural (NW)] in both dry and wet seasons. We explored biogeographic patterns of bacterial communities and the influence of landscape patterns at multi-spatial scales and water chemistry on bacterial communities. Results showed that α diversity was significantly lower in UW and AW compared to NW, particularly in the dry season. A gradient of β diversity with NW > UW > AW was observed across both seasons (p

Particle image velocimetry and numerical simulation results of juncture flows were analyzed to parametrically investigate topology transition. The vortex system evolutions from non-vortex to multi-vortex with variations in obstacle bluntness, obstacle width, flow velocity and boundary layer thickness are discussed from the perspective of velocity characteristic lines. The velocity characteristic lines of u=0, v=0, and ∇2v=0 are adopted to describe the vortex system evolution. The motions of the characteristic lines with juncture flow parameters are described in detail, and the corresponding reflections of the vortex system patterns are illustrated. A panoramic picture of the development of velocity characteristic lines corresponding to the HSV topology transition from a non-vortex to a multi-vortex system with variations in the juncture flow parameter is established. Two methods for determining the attachment/separation pattern of the most upstream singularity are proposed. One method is based on the number of intersections of the u=0 and v=0 velocity characteristic curve lines, and the other is based on the relative positions of the most upstream feet of the u=0 and v=0 loop curves with both feet attached to the wall.

Ophiopogon japonicus (Thunb.) Ker Gawl., is a traditional Chinese medicine (TCM) with a history of thousands of years. O. japonicus polysaccharides (OJPs), as one of the main active ingredient, are a kind of representative pharmacological bioactive macromolecules and mainly composed of Glc and Fru with molecular weight between 2.48 and 325 kDa. OJPs have a variety of biological activities, such as hypoglycemic, cardioprotective, immunomodulatory, improvement of obesity, and renal protective activity. In this review, the extraction, purification and structural characterization of OJPs were systematically reviewed, and its biological function, molecular mechanism and structure–activity relationship were analyzed. Additionally, this review summarized and found that structural modifications such as liposome modification, sulfation modification, and polyethylene glycol modification have improved the pharmacological activity and bioavailability of OJPs. Overall, this work will help to better understand OJPs and provide a theoretical review of their further development and utilization in the field of medicine and health food.

To accurately understand the moisture variation and drying characteristics of Lentinus edodes (L. edodes) during the drying process, the kinetics model of L. edodes with a wider application range was investigated. First, the heat pump drying kinetics model for L. edodes was fitted, verified and extended based on the orthogonal experimental data. Then, the expression of moisture ratio of L. edodes with respect to drying time, air supply temperature (AST), loading density (LD) and circulating air volume (CAV) was proposed, and interaction effects of the three key parameters on the drying time were studied based on the prediction model. The findings indicated a substantial agreement between the predicted and experimental values. The drying time could be shortened by increasing the air supply temperature and the circulating air volume or decreasing the loading density. Among these three factors, the AST had the greatest impact on drying time, followed by CAV and LD. For every 48 g/m2 reduction in LD and 11.3 m3/h increase in CAV, the drying time could be reduced by 10.5–29.9 min. Similarly, increasing the AST by 1 °C and the CAV by 11.3 m3/h could decrease the drying time by 13.7–100.6 min. The research results are helpful to optimize the drying process, improve the drying efficiency, and provide guidance and references for practical production of L. edodes HPD.

PurposeWe aimed to explore the prognostic significance of collagen content in solitary fibrous tumors (SFTs) of the central nervous system (CNS) and preliminarily investigate its relationship with magnetic resonance imaging (MRI) features of SFTs.MethodsCollagen content was identified using Masson’s trichrome staining, and quantitatively assessed. Radiomic methods were applied to extract quantitative MRI features of SFTs, which were then analyzed in relation to collagen content.ResultsThe collagen content in CNS SFTs was categorized into high- and low-content groups, with a cutoff value of 6%. Survival analysis indicated a positive correlation between collagen content and overall survival (OS). In multivariate Cox regression analysis, incorporating factors such as mitosis, necrosis, Ki67, and collagen content and other indicators, collagen content emerged as an independent prognostic factor. Collagen content demonstrated a negative correlation with tumor histological phenotype, Ki67, WHO grade, mitosis, necrosis, and brain invasion. Additionally, the signal intensity of SFTs on T2-weighted imaging (T2WI) decreased with increasing collagen content. Radiomics analysis identified 1,702 features from each patient’s region of interest, with 12 features showing significant differences between the high and low collagen content groups. Among the quantitative parameters and radiomic models, the combined T1- and T2WI models exhibited the highest diagnostic performance.ConclusionThese findings suggest that collagen content is an independent prognostic risk factor for OS. Furthermore, combined radiomic models based on T1-and T2WI sequences may offer a more comprehensive, objective, and accurate assessment of collagen content in CNS SFTs.

IntroductionPorcine circovirus type 2 (PCV2) is an important pathogen that causes diarrhea in nursery and fattening pigs, resulting in huge economic losses for commercial pig farms. Protective efficacy of vaccines is compromised by mutations in pathogens. There is an urgent need to articulate the mechanism by which PCV2 destroys the host’s intestinal mucosal barrier and to find effective therapeutic drugs. Increasing attention has been paid to the natural antiviral compounds extracted from traditional Chinese medicines. In the present study, we investigated the role of Matrine in mitigating PCV2-induced intestinal damage and enhancing autophagy as a potential therapeutic strategy in mice.MethodsA total of 40 female, specific-pathogen-free-grade Kunming mice were randomly divided into four groups with 10 mice in each group: control, PCV2 infection, Matrine treatment (40 mg/kg Matrine), and Ribavirin treatment (40 mg/kg Ribavirin). Except for the control group, all mice were injected intraperitoneally with 0.5 mL 105.4 50% tissue culture infectious dose (TCID50)/mL PCV2.ResultsWhile attenuating PCV2-induced downregulation of ZO-1 and occludin and restoring intestinal barrier function in a PCV2 Kunming mouse model, treatment with Matrine (40 mg/kg) attenuated ultrastructural damage and improved intestinal morphology. Mechanistically, Matrine reversed PCV2-induced autophagosome accumulation by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and upregulating Beclin1 protein expression, thus resisting viral hijacking of enterocyte autophagy.DiscussionOur findings demonstrate that Matrine may be a novel, potential antiviral agent against PCV2 by activating intestine cellular autophagy, which provides a new strategy for host-directed drug discovery.

ObjectiveTo explore the effectiveness of a machine learning-based multiparametric MRI radiomics nomogram for predicting the WHO/ISUP nuclear grading of clear cell renal cell carcinoma (ccRCC) before surgery.MethodsData from 86 patients who underwent preoperative renal MRI scans (both plain and enhanced) and were confirmed to have ccRCC were retrospectively collected. Based on the 2016 WHO/ISUP grading standards, patients were divided into a low-grade group (Grade I and II) and a high-grade group (Grade III and IV), and randomly split into training and testing sets at a 7:3 ratio. Radiomics features were extracted from FS-T2WI, DWI, and CE-T1WI sequences. Optimal features were selected using the Mann-Whitney U test, Spearman correlation analysis, and the least absolute shrinkage and selection operator (LASSO). Five machine learning classifiers—logistic regression (LR), naive bayes (NB), k-nearest neighbors (KNN), adaptive boosting (AdaBoost), and multilayer perceptron (MLP)—were used to build models to predict ccRCC WHO/ISUP nuclear grading. The model with the highest area under the curve (AUC) in the testing set was chosen as the best radiomics model. Independent clinical risk factors were identified using univariate and multivariate logistic regression to create a clinical model, which was combined with radiomics score (rad-score) to develop a nomogram. The model’s effectiveness was assessed using the receiver operating characteristic (ROC) curve, its calibration was evaluated using a calibration curve, and its clinical utility was analyzed using decision curve analysis.ResultsSix radiomics features were ultimately selected. The MLP classifier showed the highest diagnostic performance in the testing set (AUC=0.933). Corticomedullary enhancement level (P=0.020) and renal vein invasion (P=0.011) were identified as independent risk factors for predicting the WHO/ISUP nuclear classification and were included in the nomogram with the rad-score. The ROC curves indicated that the nomogram model had strong diagnostic performance, with AUC values of 0.964 in the training set and 0.933 in the testing set.ConclusionThe machine learning-based multiparametric MRI radiomics nomogram provides a highly predictive, non-invasive tool for preoperative prediction of WHO/ISUP nuclear grading in patients with ccRCC.

ABSTRACT Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes (Cyp7a1, Cyp27a1, Cyp8b1, and Hsd3b7) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection.IMPORTANCEThis study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.

Background: Diminished ovarian reserve (DOR), a triggering factor for female infertility, affects 10% ∼ 35% of women of reproductive age. It is still unclear whether exposure to toxic metals (including metalloid) is associated with DOR risk, especially with respect to their relationships with the clinical phenotypes of DOR. Methods: A case–control study including 439 patients was conducted, and Ba, Ni, As, Tl, Cd, Pb, Hg, Al and Cr levels in BL and FF were measured. Subsequent analyses were focused on Ba, Ni, As and Tl, which had the highest weights in the associations of the nine toxic metals (including metalloid) with DOR risk, by integrating weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) models. Conditional logistic regression models and BKMR models were used to assess the individual and combined effects of Ba, Ni, As and Tl exposures on DOR risk. Multiple linear regression models were used to investigate the relationships between toxic metal (including metalloid) levels in BL and FF and the clinical characteristics of DOR. Results: The levels of Ba [second vs. lowest tertile: adjusted odds ratio (aOR) and 95 % confidence interval (CI) = 1.97 (1.13, 3.44); highest vs. lowest tertile: aOR (95 % CI) = 2.38 (1.32, 4.26)], Ni [highest vs. lowest tertile: aOR (95 % CI) = 2.59 (1.45, 4.65)] and As [highest vs. lowest tertile: aOR (95 % CI) = 1.96 (1.18, 3.25)] in BL, and Ba [highest vs. lowest tertile: aOR (95 % CI) = 4.60 (1.68, 12.61)] in FF were significantly associated with a higher risk of DOR, respectively. The significantly positive combined effect of the four toxic metals (including metalloid) on DOR risk was exhibited when their BL levels exceeded the 25th percentile compared with their median levels. Among these, As (0.9822) and Ba (0.9704) were the primary contributors to this relationship. Similarly, this finding was confirmed by the statistical results from FF samples, with a linear positive correlation between combined exposure and DOR risk, where Ba (0.9440) was the primary contributor. Finally, elevated levels of Ba, Ni, and As in BL and Ba in FF were significantly linked to the higher follicle–stimulating hormone (FSH) levels. The levels of Ba in BL and FF, as well as As in BL, were significantly associated with the lower luteinizing hormone (LH)/FSH ratio values. Conclusion: Overall, the results of this study indicate that elevated levels of Ba, Ni, As and Tl are associated with a higher risk of DOR, whether individually or in combination, and that Ba levels in BL and FF are stable contributors. In addition, exposure to Ba, Ni, As and Tl is linked to various clinical phenotype parameters of DOR. Further research is needed to confirm these associations and to identify potential mechanisms involved.

Klebsiella pneumoniae, an emerging multidrug-resistant pathogen, exhibits hypermucoviscosity (HMV) as a critical virulence trait mediated by its capsular polysaccharide (CPS). Recent discoveries have determined acetylation as a significant modification for CPS, although its impact on HMV and virulence was previously unknown. This study elucidates the roles of two enzymes: Klebsiella pneumoniae Acetylated CPS Esterase (KpACE), an esterase that removes acetyl groups from CPS, and WcsU, an acetyltransferase that adds acetyl groups to CPS. KpACE is highly upregulated in an ompR-deficient mutant lacking HMV, and its overexpression consistently reduces HMV and diminishes virulence in a mouse model of pneumonia. The esterase domain-containing KpACE effectively deacetylates model sugar substrates and CPS-K2. Site-directed mutagenesis of the conserved catalytic histidine residue at position 370 significantly reduces its enzymatic activity. This reduction correlates with decreased HMV, affecting key virulence traits including biofilm formation and serum resistance. Similarly, a deficiency in the wcsU gene abolishes CPS acetylation, and reduces HMV and virulence. These results highlight the importance of the delicate balance between CPS acetylation by WcsU and deacetylation by KpACE in regulating the pathogenicity of K. pneumoniae. Understanding this balance provides new insights into the modulation of virulence traits and potential therapeutic targets for combating K. pneumoniae infections.

Backgrounds: Heart failure (HF) is characterized by progressive cardiac hypertrophy and fibrosis, yet the underlying pathological mechanisms remain unclear. Exosomes are pivotal in cellular communication and are key signaling carriers in HFs. This study investigated the roles of exosomes in HF. Methods: Eight-week-old male mice were divided into three groups: a control group, an Ang II group receiving angiotensin II (Ang II) infusion for 4 weeks, and an Ang II + DMA group receiving Ang II and dimethyl amiloride (DMA) infusion. This study examined the associations between cardiac injury, exosomes, and their substrate Shh. Furthermore, we conducted cellular experiments to assess the effects of Ang II-induced injury in primary cardiomyocytes on other cardiomyocytes and fibroblasts, and to test the therapeutic effects of the exosome inhibitor DMA and the Shh signaling inhibitor cyclopamine (CPN). Results: Ang II-induced cardiac hypertrophy and fibrosis, which were accompanied by exosome secretion and Shh upregulation in vivo. DMA relieved these cardiac lesions. Furthermore, cellular experiments revealed that Ang II-induced cardiomyocytes hypertrophy and activated cardiac fibroblasts by promoting the release of exosomes containing Shh/N-Shh/Gli1. Both DMA and CPN nullified fibroblast activation and proliferation. Conclusions: Ang II-induced cardiomyocyte injury leads to cardiac hypertrophy and fibrosis through the release of exosomes carrying Shh signaling. The suppression of exosome secretion or the Shh pathway could offer new strategies for treating HF.

ABSTRACT Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in de novo guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether in vivo inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy in vivo against Acinetobacter baumannii mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of A. baumannii, Staphylococcus aureus, and Escherichia coli GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear in vivo efficacy of these small molecule GuaB inhibitors in a model of A. baumannii infection validates GuaB as an essential antibiotic target.IMPORTANCEThe emergence of multidrug-resistant bacteria worldwide has renewed interest in discovering antibiotics with novel mechanism of action. For the first time ever, we demonstrate that pharmacological inhibition of de novo guanine biosynthesis is bactericidal in a mouse model of Acinetobacter baumannii infection. Structural analyses of novel inhibitors explain differences in biochemical and whole-cell activity across bacterial clades and underscore why this discovery may have broad translational impact on treatment of the most recalcitrant bacterial infections.

Due to the rapid loss of biodiversity and financial and human resource limitations, there is an urgent need to prioritize biodiversity conservation. Setting conservation priorities is also an important part of conservation biology. Species abundance, richness and International Union for Conservation of Nature (IUCN) ranks are the most commonly used methods for setting conservation priorities, but with the development of bioinformatics, many studies have also demonstrated the utility of incorporating phylogenetic diversity into species prioritization, with evolutionary distinctiveness (ED) and evolutionarily distinct and globally endangered (EDGE) being widely used to determine the prioritization of species for conservation, where ED measures the contribution of species to the overall evolutionary history, and EDGE considers both evolutionary distinctiveness and IUCN ranks. In this study, based on the vascular plant distribution data collected on the Qinghai-Tibet Plateau (QTP), we determined the conservation priorities of plants on the QTP according to ED and EDGE2 considering four extinction risk transformations, investigated the relationship between IUCN ranks and ED, evaluated the effects of unassessed (NA) data deficiency (DD) species on EDGE rankings, and determined the conservation efficiency of the QTP conservation network in areas with evolutionary history and explored the possibility of incorporating evolutionary history into species conservation priorities. The results showed that there was no significant relationship between the ED of vascular plants and the IUCN ranks on the QTP; the results of EDGE2 showed that the top 25 species, with 14 species common to all four transformations, possessed both high ED and IUCN ranks; when EDGE2 containing DD and NA species showed that DD and NA species accounted for a large percentage of the top 25 species for all four transformations, suggesting that they may have significant potential for evolutionary history conservation; that the conservation priority areas for endemic seed plants of the QTP are located in the Hengduan Mountains, the eastern Yarlung Zangbo River, the southern Qionglai Mountains, the western Gangdise Mountains and the southern Kunlun Mountains; and that the QTP conservation networks protect the only 38.2 % of the areas rich in evolutionary history. These results emphasize the need to incorporate evolutionary information into conservation biology, but it should also be considered in conjunction with existing taxonomic diversity methods as a complementary conservation tool to provide a new perspective on the conservation of QTP plant diversity.

Changes in gluten during the freezing process could cause a deterioration in dough quality, which would be solved by electrostatic field treatment. This paper investigated the effects of electrostatic field assisted freezing (EFAF) on the functional properties, structural characteristics and aggregation behavior of gluten. The results showed that EFAF improved the functional properties of gluten with enhanced water holding, emulsifying and foaming properties. When the electrostatic field was applied, the α-helix content and g-g-g conformation of gluten proteins increased with a maximum of 27.50 % and 40.05 %, respectively, which were significantly different from the control (P

Background: Existing deep learning methods, such as generative adversarial network (GAN) technology, face challenges when dealing with mixed datasets, which involve a combination of Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT). This issue significantly complicates the application of dose prediction in the field of radiotherapy. In this study, we propose a novel approach called beam channel GAN (Bc-GAN) to address the task of radiation dose prediction for mixed datasets. Bc-GAN introduces a dose prediction calculation method that requires less precision. By defining an approximate range for dose prediction, Bc-GAN limits the physical range of GAN prediction, resulting in more reasonable dose distribution predictions. Methods: We adopt a beam angle weighting method to determine the beam angle in the dose calculation. The dose of the beam with the highest weight is calculated using medical images and is then inputted into the artificial intelligence dose prediction model as the input channel. Additionally, we collect data from a total of 346 patients with Cervical Cancer (CC) for dataset. After cleaning the data, we exclude 51 cases with incomplete organ delineation, leaving us with 295 cases (IMRT: VMAT = 137:158) randomly divided into three sets: the training set, the validation set, and the test set, with proportions of 205:60:30, respectively. The assessment of model predictions was conducted via an analysis of dose distributions on the tomographic plane, dose volume histogram (DVH), and dosimetric parameters within the target zones and organs at risk (OAR). Results: After DVH analysis, minimal discrepancy was found between predicted and actual dose distributions in PTV and OAR. The predicted distribution aligned with clinical standards. Dosimetric parameters for PTV were generally lower in the predicted model, except for homogeneity index (HI) (0.238 ± 0.024, P = 0.017) and Dmax (53.599 ± 0.710 Gy, P = 1.8e-05). The prediction model varied in estimating doses for six organs. Specifically, small intestine showed higher V20 (67.92 ± 51.64 %, P = 0.019) and V30 (57.171 ± 1.213 %, P = 0.024) than manual planning. A similar trend was seen in colon's V30 (37.13 ± 61.14 %, P = 0.016). However, predicted bladder V30 (87.51 ± 41.44 %, P = 2.03e-16) was lower, indicating significant dosimetric differences. Conclusion: Overall, this study presents an innovative prediction method for CC in radiotherapy using the Bc-GAN model, addressing the challenges posed by different radiotherapy techniques. The proposed approach allows IMRT and VMAT in radiotherapy to be used as training sets, enabling the potential for large-scale engineering and commercialization applications of artificial intelligence (AI). The Bc-GAN-based prediction method for CC in radiotherapy not only reduces the amount of data needed for the training set but also expedites the model generation process. This approach can be applied to guide the development of clinical radiation therapy plans. Furthermore, future studies should consider extending the dose prediction method to encompass other types of tumors.

Summary: Mesoscale to nanoscale three-dimensional (3D) fabrication mostly requires complicated industry processing techniques. Here, we present a protocol for 3D shaping control by solidifying a water-based TiO2 nanofluid drop on a polygonal wettability-patterned surface. We detail the steps for preparing stable TiO2 nanofluid and wettability-patterned surfaces. We then describe the experimental procedure to obtain various and precise 3D morphologies by adjusting the deposited TiO2 nanofluid drop volume. This protocol provides a promising technique for future 3D manufacturing.For complete details on the use and execution of this protocol, please refer to Jiang et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.