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Abstract Background MicroRNAs (miRNAs) are pivotal in the initiation and progression of complex human diseases and have been identified as targets for small molecule (SM) drugs. However, the expensive and time-intensive characteristics of conventional experimental techniques for identifying SM-miRNA associations highlight the necessity for efficient computational methodologies in this field. Results In this study, we proposed a deep learning method called Multi-source Data Fusion and Graph Neural Networks for Small Molecule-MiRNA Association (MDFGNN-SMMA) to predict potential SM-miRNA associations. Firstly, MDFGNN-SMMA extracted features of Atom Pairs fingerprints and Molecular ACCess System fingerprints to derive fusion feature vectors for small molecules (SMs). The K-mer features were employed to generate the initial feature vectors for miRNAs. Secondly, cosine similarity measures were computed to construct the adjacency matrices for SMs and miRNAs, respectively. Thirdly, these feature vectors and adjacency matrices were input into a model comprising GAT and GraphSAGE, which were utilized to generate the final feature vectors for SMs and miRNAs. Finally, the averaged final feature vectors were utilized as input for a multilayer perceptron to predict the associations between SMs and miRNAs. Conclusions The performance of MDFGNN-SMMA was assessed using 10-fold cross-validation, demonstrating superior compared to the four state-of-the-art models in terms of both AUC and AUPR. Moreover, the experimental results of an independent test set confirmed the model’s generalization capability. Additionally, the efficacy of MDFGNN-SMMA was substantiated through three case studies. The findings indicated that among the top 50 predicted miRNAs associated with Cisplatin, 5-Fluorouracil, and Doxorubicin, 42, 36, and 36 miRNAs, respectively, were corroborated by existing literature and the RNAInter database.

Pleurotus pulmonarius, commonly known as the mini oyster mushroom, is highly esteemed for its crisp texture and umami flavor. Limited genetic diversity among P. pulmonarius cultivars raises concerns regarding its sustainable industrial production. To delve into the maternal genetic diversity of the principal P. pulmonarius cultivars, 36 cultivars and five wild isolates were subjected to de novo sequencing and assembly to generate high-quality mitogenome sequences. The P. pulmonarius mitogenomes had lengths ranging from 69,096 to 72,905 base pairs. The mitogenome sizes of P. pulmonarius and those of other mushroom species in the Pleurotus genus showed a significant positive correlation with the counts of LAGLIDAG and GIY-YIG homing endonucleases encoded by intronic open reading frames. A comparison of gene arrangements revealed an inversion of a fragment containing atp9-nad3-nad2 between P. pulmonarius and P. ostreatus. The mitogenomes of P. pulmonarius were clustered into three distinct clades, two of which were crowded with commercial cultivars. Clade I, all of which possess an inserted dpo gene, shared a maternal origin linked to an ancestral cultivar from Taiwan. Primers were designed to target the dpo gene, potentially safeguarding intellectual property rights. The wild isolates in Clade III exhibited more divergent mitogenomes, rendering them valuable for breeding.

Abstract Silver deposits have long been considered to form due to the direct precipitation of silver minerals from aqueous fluids, in which the metal is transported as chloride and/or bisulfide complexes. Ultra-high-grade silver ores have silver contents up to tens of weight-percent in the form of silver sulfides and native silver. Ore-forming fluids of most silver deposits, however, typically contain low silver contents of parts per million silver. The challenge is to explain how fluids with such low concentrations of silver can form ultra-high-grade silver ores. Here, we present direct mineralogical evidence from natural samples showing that the high-grade silver ores form from the aggregation of silver sulfide nanoparticles through intermediate microparticles and dendrites to acanthite crystals. Native silver grows from silver sulfides via solid-state silver ion aggregation. This study traces the formation of silver sulfides from their nanoparticulate precursors, thereby providing insights into the genesis of ultra-high-grade silver ores in a variety of metallogenic settings.

Abstract Applying anammox to municipal wastewater treatment promises enormous energy and resource savings; however, seasonally cold conditions pose a considerable challenge, impeding its future applications towards non-tropical regions. In this study, we establish a pilot-scale wastewater treatment plant (50 m3/d) in northern China and implement the partial denitrification coupling anammox process on actual municipal wastewater. Despite seasonal cooling, the nitrogen removal efficiency remains high, ranging from 75.0 ± 4.6% at 27.8–20.0 °C to 70.4 ± 4.5% at 10–7.5 °C. This process exhibits remarkable low-temperature tolerance, achieving an in-situ anammox rate of 32.7 ± 4.7 g-N/(m3·d) at 10–7.5 °C and contributing up to 39.7 ± 6.7% to nitrogen removal. Further 15N stable isotope tracing and kinetic tests reveal that the partial denitrification is capable of supplying increasingly abundant NO2 - to anammox with decreasing temperature, enabling robust mainstream anammox against seasonal cooling. From 27.8 °C to 7.5 °C, anammox bacteria not only survive but thrive under mainstream conditions, with absolute and relative abundances increasing by 429.1% and 343.5%, respectively. This pilot-scale study sheds fresh light on extending mainstream anammox towards non-tropical regions, taking a necessary step forward toward the sustainability goals of the wastewater treatment sector.

Abstract Background Skin cutaneous melanoma (SKCM) poses a significant public health challenge due to its aggressive nature and limited treatment options. To address this, the study introduces the Tumor Mutational Burden-Derived Immune lncRNA Prognostic Index (TILPI) as a potential prognostic tool for SKCM. Methods TILPI was developed using a combination of gene set variation analysis, differential expression analysis, and COX regression analysis. Additionally, functional experiments were conducted to validate the findings, focusing on the effects of STARD4-AS1 knockdown on SKCM tumor cell behavior. These experiments encompassed assessments of tumor cell proliferation, gene and protein expression, migration, invasion, and in vivo tumor growth. Results The results demonstrated that knockdown of STARD4-AS1 led to a significant reduction in tumor cell proliferation and impaired migration and invasion abilities. Moreover, it resulted in the downregulation of ADCY4, PRKACA, and SOX10 gene expression, as well as decreased protein expression of ADCY4, PRKACA, and SOX10. In vivo experiments further confirmed the efficacy of STARD4-AS1 knockdown in reducing tumor growth. Conclusions This study elucidates the mechanistic role of STARD4-AS1 and its downstream targets in SKCM progression, highlighting the importance of the ADCY4/PRKACA/SOX10 pathway. The integration of computational analysis with experimental validation enhances the understanding of TILPI and its clinical implications. Overall, the findings underscore the potential of novel computational frameworks like TILPI in predicting and managing SKCM, particularly through targeting the ADCY4/PRKACA/SOX10 pathway.

Realizing green and low-carbon development will be a new requirement facing the coal industry. In order to address this problem, this paper proposed a method of preparing foam concrete using a supercritical CO2 phase change foaming technology, and a Portland cement-based supercritical CO2 foamed concrete with both high pore structure and carbon sequestration capacity was prepared. The effects of supercritical CO2 on the dry density, pore structure and carbon sequestration capacity of the material and its mechanism were investigated. The experimental results revealed that the supercritical CO2 phase change foamed concrete preparation process is a temperature-pressure dynamic coordination process considering Portland cement properties and its reaction properties with CO2 mineralization. The mechanism of Portland cement-based foamed concrete prepared by the supercritical CO2 phase change foaming technology may be divided into four stages: CO2-cement slurry coexistence, CO2-cement slurry co-solution, supercritical CO2-cement slurry co-solution, and unpressurized foaming. Increasing the experimental pressure can increase the CO2 concentration in the supercritical CO2-concrete system and reduce the dry density of supercritical CO2-foamed concrete, which varies from 787.14 to 993.52 kg/m3 with a range of 8.28% to 19.20%. The development of porosity of supercritical CO2 foamed concrete was affected by the diffusion-dissolution behavior of CO2 in the supercritical CO2-concrete system, and its porosity was 47.87%−89.79%. Increasing the experimental pressure and optimizing the holding time are the development direction for preparing supercritical CO2 foamed concrete with high porosity. The supercritical CO2 foamed concrete has uniform, regular and independent circular pores with approximately the same pore diameter of 0.2 mm. Increasing the experimental pressure can promote the degree of CO2 mineralization reaction and effectively optimize the structure and distribution density of the pores. Each tonne of supercritical CO2 foamed concrete has a carbon sequestration capacity of 6.32%−10.36% in the skeleton and 0.98−2.27 kg in the pore, which has obvious carbon sequestration potential, but the preparation process and parameters still need to be further improved. The results show that the supercritical CO2 foamed concrete is expected to be developed into a functional material with near-zero-carbon for mining, which is of great significance for realizing the carbon reduction at the source of coal power integration base.

Objective To explore the effect of extended care on improving the compliance, efficacy and quality of life of antiviral therapy in elderly patients with acquired immunodeficiency syndrome (AIDS) . Methods A total of 200 elderly patients with acquired immunodeficiency syndrome who received initial antiviral therapy in Beijing You'an Hospital from January 2015 to December 2021 were selected as the study subjects and randomly divided into the control group and the test group according to the lottery method, with 100 cases in each group. The control group received routine care and health education, and the experimental group was given extended care on the basis of the control group. After 1 year of follow-up, medication compliance, efficacy, and quality of life were compared between the two groups. Results During 1-year follow-up, the medication compliance of the test group was higher than that in the control group, and the difference was statistically significant (P < 0.05); the increase of CD4+ T lymphocyte count in the test group was higher than that in the control group (P < 0.05); the viral load was undetectable after treatment in both groups. The scores of physical domain, psychological domain, social relationship domain and environmental domain of quality of life in the test group were higher than those in the control group, and the differences were statistically significant (P < 0.05) . Conclusion Extended care is beneficial to improve the medication compliance and antiviral effect of elderly patients with acquired immunodeficiency syndrome, and improve the quality of life of patients. It is worthy of clinical promotion and application.

ObjectiveWe aimed to compare the perioperative outcomes and postoperative complications of laparoscopic radical antegrade modular pancreatosplenectomy (L-RAMPS) versus laparoscopic distal pancreatosplenectomy (L-DPS) for left-sided pancreatic cancer through a meta-analysis.MethodsA systematic review and meta-analysis, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were performed. Literature searches were conducted in PubMed, Web of Science, Cochrane Library, and Embase for studies published from their inception up to June 14th, 2024.ResultsA total of three retrospective studies involving 242 patients were included in this meta-analysis, with 116 patients in the L-RAMPS group and 126 in the L-DPS group. The meta-analysis results indicated that L-RAMPS was associated with the retrieval of more lymph nodes (MD: 3.06; 95% CI: 2.51 to 3.62, p < 0.00001) and longer operative time (MD: 20.05; 95% CI: 13.97 to 26.12, p < 0.00001) compared to L-DPS for left-sided pancreatic cancer patients. However, no significant differences were observed between the two groups in terms of R0 resection margins, the incidence of pancreatic fistula (Grade B and C), postpancreatectomy hemorrhage, or postoperative complications (Clavien-Dindo Grades II and III).ConclusionsIn patients with left-sided pancreatic cancer, L-RAMPS resulted in the retrieval of more lymph nodes, a longer operative time, and a similar incidence of postoperative complications compared to L-DPS. Larger sample sizes, extended follow-up periods, and well-conducted randomized controlled trials are needed to further validate these findingsSystematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=558977, identifier CRD42024558977.

IntroductionPneumocystis pneumonia (PCP) is a common and serious complication of HIV/AIDS, with a higher prevalence in patients not receiving antiretroviral therapy. Due to the high mortality rate of PCP, accurate prediction of its case fatality rate is very important for clinical treatment. We aimed to develop a risk model for the near-term prognosis of people with HIV/AIDS and PCP and verify its effectiveness.MethodsThis single-center, retrospective observational study was conducted at Beijing Youan Hospital from January 2012 to October 2022. 972 AIDS patients with Pneumocystis pneumonia met our criteria were recruited. The patients were divided into death group and survival group according to clinical outcome during hospitalization. Data of the two groups were collected including general information and laboratory test results. 53 medical characteristics of the two groups were collected. Prediction variables were screened with Multivariate logistic regression analysis and Lasso regression model. We used ROC curve to identify the discrimination of training and testing data sets. The Shapley Additive exPlanation (SHAP) method was applied to explain the final model and the weights of features.ResultsThe overall mortality rate among hospitalized patients was 17.8%. We found that the best prediction effect can be obtained when ALB, PO2, TBIL, LDH, CD4+ T lymphocyte counts are incorporated into the PCP risk prediction model. The model had a perfect discrimination with AUC of 0.994 and 0.947 in training and validation cohorts. The prognosis risk grade was divided into three grades: low-risk group (0-25 points with mortality of 5.9%), moderate-risk group (25-50 points with mortality of 45.1%) and high-risk group (above 50 points with mortality of 80%). There is a statistically significant difference in mortality among these three grades (χ2 = 419.271, P

Objectives To evaluate the feasibility, efficacy, and safety of radiofrequency ablation (RFA) for solitary T1N0M0 papillary thyroid carcinoma (PTC) in the danger triangle area.Methods 94 participants (mean age 44.45 ± 13.08; 73 females) with solitary T1N0M0 PTC in the danger triangle area who underwent percutaneous RFA at the hospital from January 2018 to April 2020 were retrospectively analyzed. Key ablation procedures included sufficient paratracheal fluid isolation, low-power, and short active tip (5 mm working electrode). Tumor size changes at different time points after RFA, technical success rates, tumor disappearance, disease progression, and complications were recorded and compared.Results Contrast-enhanced ultrasonography revealed that complete tumor ablation was performed with a 100% success rate in these patients. Post-ablation, the maximum diameter and volume of the ablation zone increased at the first and third month (p

Abstract Purpose To summarize the abdominal computed tomography (CT) imaging and clinicopathological data of patients with SPNs of the pancreas and analyze the accuracy of preoperative CT diagnosis and features. Materials and methods Between June 2006 and June 2023, CT images of 120 histopathologically proven SPNs in the pancreas were retrospectively reviewed. Fifteen features, including age, sex, and CT-determined features, were included in a multiple stepwise regression analysis. The correlations between features and SPNs, including odds ratios (ORs) and 95% confidence intervals (CIs), were evaluated. Results Among the 120 patients, the diagnostic accuracy of CT was 43.3%. The baseline CT results of patients with a correct diagnosis and misdiagnosis revealed significant differences in sex (P = 0.043), age (P = 0.004), boundary (P = 0.037) and encapsulation (P = 0.002) between the two groups. The preoperative imaging diagnostic accuracy was significantly greater in females than in males (47.9% vs. 25.0%, P = 0.043). The immunohistochemical indices did not significantly differ between the two groups. The results of univariate analysis revealed significant differences in sex (P = 0.048), age (P = 0.014), tumor length (P = 0.023), tumor boundaries (P = 0.039) and capsule type (P = 0.003). The results of multivariate analysis revealed that encapsulation was closely related to the diagnostic accuracy of CT (P = 0.04). Conclusions The accuracy of CT in the diagnosis of SPNs is low, but a length‒diameter ratio of the tumor approaching 1.0, encapsulation and clear boundaries are important CT-determined features. The capsule is an independent CT predictor in the diagnosis of SPNs.

Abstract Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3’ untranslated region of Ckip-1 (Ckip-1 3’UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3’UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3’UTR in treating SD-induced heart disease.

Abstract. Background:. Antiretroviral therapy (ART) was often associated with dyslipidemia among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. This study aimed to assess treatment-naïve adult male patients with HIV/AIDS who initiated ART with either co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) or lamivudine, efavirenz, and tenofovir disoproxil fumarate (3TC+EFV+TDF), monitoring at weeks 4, 12, 24, and 48. Methods:. A case-control retrospective study was conducted. The newly diagnosed HIV-infected individuals attending the sexual transmission disease (STD)/AIDS clinic of Beijing Youan Hospital, Capital Medical University, from January to December 2021. The patients were divided into BIC/FTC/TAF group or 3TC+EFV+TDF group. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) at different time points over 48 weeks between two groups were compared. A multivariate Cox regression model was used to identify relevant influencing factors for the population at high risk of increased LDL-C. Results:. A total of 870 participants, with 510 in BIC/FTC/TAF group and 360 in 3TC+EFV+TDF group. There were no statistically significant differences in median age, baseline CD4/CD8 ratio, median body mass index (BMI) between the two groups. In both two groups, levels of TG, TC, and LDL-C were higher at 4 weeks, 12 weeks, and 24 weeks of treatment (all P 0.05). In addition, the differences in average changes of the level of TG, TC, HDL-C, and LDL-C from weeks 4, 12, 24, and 48 to baseline between two groups were not statistically significant (all P >0.05). Multivariate Cox proportional risk model analysis showed that initiating ART with HIV RNA ≥105 copies/mL (compared with

Boundary identification of field sources is an indispensable task for interpreting field data. Initially, people used the distribution characteristics of data to obtain boundary information of field sources, making it difficult to identify weak anomalies amidst strong background anomalies. To address this issue, automatic control filters based on a certain window size were employed to identify the distribution of field sources. However, this method's results heavily relied on the window size and were not well applicable to complex anomalies. In recent years, features reflecting the boundary information of field sources have mainly been derived from the derivatives of scalar field data. Then, the correspondence between imaging results and boundaries is utilized to identify the horizontal boundaries of field sources. Specifically, extreme values of magnetic anomaly horizontal derivatives and zero values of vertical derivatives correspond to geological body boundaries. Existing boundary identification methods mainly utilize a balanced boundary identification filter composed of the ratio of first-order horizontal and vertical derivatives to delineate the positions of geological bodies, but the method has lower resolution and generality. Therefore, this paper proposes combining boundary detection filters based on ratios of derivatives of different orders with multiscale unsupervised deep learning. This approach utilizes different orders of derivative ratios to obtain higher-resolution edge imaging results. Additionally, a combination of Deep Image Prior (DIP) and Generative Adversarial Network-None Local (GAN-NL) networks for multiscale unsupervised deep learning is established to determine the horizontal position of sources based on extreme values of edge imaging results. The multiscale DIP network is used to identify the source position, and a self-attention mechanism neural network is added to the DIP network to enhance its learning ability, which can remove noise without requiring a large amount of data label.

The thermodynamic contribution to extraction of medical devices by organic solvents as a first sample preparation step in chemical characterization studies is evaluated by Abraham's solvation parameter model using five representative materials (low density polyethylene or LDPE, silicone, polyurethane or PU, polyoxymethylene or POM, and polyacrylate or PA) and ten solvents (methanol, ethanol, isopropanol, acetonitrile, ethylene glycol, acetone, butanone, hexane, olive oil, and triolein). The Abraham's model is used to predict the material-solvent partition system coefficients by the corresponding partition system constants and representative extractables. The partition system constants are indirectly derived by a “thermodynamic circle conversion” method, based on material-water partition systems and solvent- water partition systems or material-air partition systems and solvent-air water partition systems. The material-solvent partition coefficient, PM/Solvent=CM/CSolvent, defined as the concentration in the material phase divided by the concentration in the solvent phase, is used as the solvent extraction strength. log(PM/Solvent) values are predicted for all material-solvent pairs using the representative extractables, mostly from Wayne state university experimental descriptor database (WSUEDD). The predictive log(PM/Solvent) values of material-solvent pairs are considered as the upper bound, indicating the significance of partitioning effect in solvent extraction. The calculation results using water-based or air-based partition systems are also compared. The predictive results are discussed in relation to the solvent-material interaction or swelling as well. Several conclusions can be drawn from this study. First, the predictive consistency of two conversion systems (water-based or air-based) is established, indicating the accuracy and robustness of Abraham's model. Second, the predicted partition coefficients are confirmed by available experimental values (LDPE and silicone), and the predicted solvent extraction strengths are supported by available experimental extraction data. Third, the kinetic effect, rather than the thermodynamic effect, is the dominant extractables release process in sample preparation step of chemical characterization studies. The solvent selection in these studies should be optimized based mainly on the diffusional kinetics and solvent-material interactions (swelling effect). Fourth, acetone and butanone can be the general-purpose solvent for the extraction of all materials, thereby eliminating the need for three solvents in chemical characterization studies. Finally, Abraham's solvation parameter model is demonstrated as an invaluable tool in understanding and differentiating the solvent extraction processes.

Emulsions, particularly in the pharmaceutical, cosmetic, and food industries, are essential for the delivery and stabilization of active ingredients. Due to their structural complexity—including variations in droplet size, phase distribution, and interfacial properties—characterizing emulsions is essential for optimizing their performance and stability. Existing reviews tend to focus on specific emulsion types, properties, or individual characterization techniques, often failing to provide a holistic assessment. Consequently, there is a critical need for a comprehensive review that integrates various characterization methods. This review addresses this gap by systematically evaluating key techniques, including scattering methods (dynamic light scattering, small-angle x-ray scattering), spectroscopic techniques (Fourier transform infrared and nuclear magnetic resonance spectroscopy), microscopy methods (scanning electron microscopy, confocal laser scanning microscopy), and rheometry. By consolidating the strengths and limitations of each method, this review offers a unified framework to guide researchers in selecting appropriate techniques for characterizing emulsions, ultimately contributing to the optimization of their structure, properties, and performance across diverse applications.

The Abraham's solvation parameter model is an important tool to model and predict distribution properties of compounds in numerous partitioning systems in chemistry, environmental chemistry, medicine, and biology. The evaluation of the distribution properties in extractables and leachables (E&L) studies in pharmaceutical and medical device industries is another major application of this model. This tutorial is aimed at illustrating the applications of the model in E&L studies. Specific examples of the application illustrated in this tutorial include: (a) establishment of equivalent or similar solvents; (b) determination of polarity of solvents, biological tissues, and materials; (c) development of drug product simulating solvents; (d) understanding solvent extraction power for a material; (e) selection of solvent and standards in pretreatment of extraction samples; and (f) chromatography retention prediction for E&L.

Differentiated thyroid cancers (DTCs) constitute the primary histological subtype within thyroid cancer. Due to DTCs’ distinctive radioiodine (RAI) uptake mechanism, standard treatment involving surgery, with or without adjunctive therapy using RAI and levothyroxine inhibition, typically yields favorable prognoses for the majority of patients with DTCs. However, this favorable outcome does not extend to individuals with decreased RAI uptake, termed radioiodine-refractory thyroid cancers (RAI-RTCs). Recent research has revealed that the genetic mutations and gene rearrangements affecting sites such as RTKs, RAS, BRAF and TERTp lead to structural and functional abnormalities in encoded proteins. These abnormalities aberrantly activate signaling pathways like the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-hydroxykinase (PI3K) signaling pathways, resulting in thyroid cells dedifferentiation, sodium/iodide symporter (NIS) dysfunction, and consequent the RAI-refractory nature of DTCs. Targeted therapy tailored to mutations presents a promising avenue for the treatment of RAI-RTCs. Lenvatinib and sorafenib, multi-kinase inhibitors, represent the standard first-line systemic treatment options, while cabozantinib is the standard second-line treatment option, for this purpose. Furthermore, ongoing clinical trials are exploring selective kinase inhibitors, immune checkpoint inhibitors, and combination therapies. Notably, numerous clinical trials have demonstrated that selective kinase inhibitors like BRAF, MEK and mTOR inhibitors can restore RAI uptake in tumor cells. However, further validation through multicenter, large-sample, double-blinded randomized controlled trials are essential. Enhanced treatment strategies and innovative therapies are expected to benefit a broader spectrum of patients as these advancements progress.

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare genetic disease, characterized by co-occurrence of several lesions of the endocrine system. In MEN1, the pathogenic MEN1 gene mutations lead to the Abnormal expression of menin, a critical tumor suppressor protein. We here reported a case of a 14‐year‐old male with insulinoma and primary hyperparathyroidism. Genetic testing demonstrated a novel heterozygote variant c.587delA of MEN1, resulting in the substitution of the 196th amino acid, changing from glutamic acid to glycine, followed by a frameshift translation of 33 amino acids. An identical variant was identified in the proband’s father, who was further diagnosed with hyperparathyroidism. To the best of our knowledge, this is the first report of MEN1 syndrome caused by the c.587delA MEN1 variant. Observations indicated that, despite sharing the same MEN1 gene change, family members exhibited diverse clinical phenotypes. This underscored the presence of genetic anticipation within the familial context.

Abstract Zinc anodes of zinc metal batteries suffer from unsatisfactory plating/striping reversibility due to interfacial parasitic reactions and poor Zn2+ mass transfer kinetics. Herein, methoxy polyethylene glycol‐phosphate (mPEG‐P) is introduced as an electrolyte additive to achieve long anti‐calendar aging and high‐rate capabilities. The polyanionic of mPEG‐P self‐assembles via noncovalent‐interactions on electrode surface to form polyether‐based cation channels and in situ organic–inorganic hybrid solid electrolyte interface layer, which ensure rapid Zn2+ mass transfer and suppresses interfacial parasitic reactions, realizing outstanding cycling/calendar aging stability. As a result, the Zn//Zn symmetric cells with mPEG‐P present long lifespans over 9000 and 2500 cycles at ultrahigh current densities of 120 and 200 mA cm−2, respectively. Besides, the coulombic efficiency (CE) of the Zn//Cu cell with mPEG‐P additive (88.21%) is much higher than that of the cell (36.4%) at the initial cycle after the 15‐day calendar aging treatment, presenting excellent anti‐static corrosion performance. Furthermore, after 20‐day aging, the Zn//MnO2 cell exhibits a superior capacity retention of 89% compared with that of the cell without mPEG‐P (28%) after 150 cycles. This study provides a promising avenue for boosting the development of high efficiency and durable metallic zinc based stationary energy storage system.

Abstract Background The correlation between the triglyceride-glucose index (TyG) and the prognosis of ischemic stroke has been well established. This study aims to assess the influence of the TyG index on the clinical outcomes of critically ill individuals suffering from intracerebral hemorrhage (ICH). Methods Patients diagnosed with ICH were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Various statistical methods, including restricted cubic spline (RCS) regression, multivariable logistic regression, subgroup analysis, and sensitivity analysis, were employed to examine the relationship between the TyG index and the primary outcomes of ICH. Results A total of 791 patients from MIMIC-IV and 1,113 ones from eICU-CRD were analyzed. In MIMIC-IV, the in-hospital and ICU mortality rates were 14% and 10%, respectively, while in eICU-CRD, they were 16% and 8%. Results of the RCS regression revealed a consistent linear relationship between the TyG index and the risk of in-hospital and ICU mortality across the entire study population of both databases. Logistic regression analysis revealed a significant positive association between the TyG index and the likelihood of in-hospital and ICU death among ICH patients in both databases. Subgroup and sensitivity analysis further revealed an interaction between patients' age and the TyG index in relation to in-hospital and ICU mortality among ICH patients. Notably, for patients over 60 years old, the association between the TyG index and the risk of in-hospital and ICU mortality was more pronounced compared to the overall study population in both MIMIC-IV and eICU-CRD databases, suggesting a synergistic effect between old age (over 60 years) and the TyG index on the in-hospital and ICU mortality of patients with ICH. Conclusions This study established a positive correlation between the TyG index and the risk of in-hospital and ICU mortality in patients over 60 years who diagnosed with ICH, suggesting that the TyG index holds promise as an indicator for risk stratification in this patient population.

Abstract Introduction Sepsis is a severe disease with a complex pathogenesis and is an important factor in the mortality of patients in intensive care units (ICUs). The administration of vitamin C and its combination treatment in sepsis was not supported by the results of multiple randomized controlled clinical trials. However, the efficacy of a higher vitamin C dose in treating patients with sepsis remains unclear. Therefore, the effectiveness of administering a larger dosage of vitamin C to patients with sepsis remains unclear. Methods and Analysis The Clinical Efficacy of Megadose Vitamin C in Sepsis (CEMVIS) trial is a multicenter, single-blind, randomized, placebo-controlled trial with 234 individuals with sepsis. The following adult patients will be enrolled: those with procalcitonin (PCT) ≥ 2 ng/mL and sepsis 3.0 diagnostic criteria. Patients will be randomly assigned to receive 12 g vitamin C or the same volume of 5% glucose injection intravenously pumped every 12 h for 4 days or up to the moment they are discharged from ICU. The primary outcome will be the mortality within 28 days. Secondary outcomes will mainly include protection and support of organ functions, improvement in inflammatory status, and length of ICU stay. Moreover, adverse events and serious adverse events will be meticulously recorded. Ethics This study was approved by the Clinical Ethics Committee of Zhujiang Hospital of Southern Medical University (2020-KY-069-05). The trial results will be published in peer-reviewed journals or at national or international conferences. Trial registration clinicaltrials.gov, NCT05194189, Registered 3 January 2022, URL: https://www.clinicaltrials.gov .

Abstract Dynamic microscale droplets produced by liquid–liquid phase separation (LLPS) have emerged as appealing biomaterials due to their remarkable features. However, the instability of droplets limits the construction of population-level structures with collective behaviors. Here we first provide a brief background of droplets in the context of materials properties. Subsequently, we discuss current strategies for stabilizing droplets including physical separation and chemical modulation. We also discuss the recent development of LLPS droplets for various applications such as synthetic cells and biomedical materials. Finally, we give insights on how stabilized droplets can self-assemble into higher-order structures displaying coordinated functions to fully exploit their potentials in bottom-up synthetic biology and biomedical applications.

Abstract Patients suffering from osteoporotic fractures often require effective fixation and subsequent bone repair. However, the currently available materials are functionally limited and often fail to improve outcomes in this patient population. In this study, we developed orthopedic adhesives doped with romosozumab-loaded mesoporous bioactive glass nanoparticles to aid in osteoporotic fracture fixation and restore dysregulated bone homeostasis. These adhesives were designed to promote osteoblast formation while simultaneously inhibiting osteoclastic bone-resorbing activity, thus working synergistically to promote the healing of osteoporotic fractures. Orthopedic adhesives exhibit injectability, reversible adhesiveness, and malleability, enhancing their adaptability to complex clinical scenarios. Furthermore, the release of romosozumab from mesoporous bioactive glass nanoparticles accelerated osteogenesis and inhibited osteoclastogenesis, delaying the bone resorption process. This dual action contributes to the regulation of bone regeneration and remodeling. Notably, our orthopedic adhesive could restore the disrupted bone homeostasis associated with osteoporotic fractures.

Cancer patients by immune checkpoint therapy have achieved long-term remission, with no recurrence of clinical symptoms of cancer for many years. Nevertheless, more than half of cancer patients are not responsive to this therapy due to immune exhaustion. Here, we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod (PD1-Imi Exo) for boosting response of cancer immune checkpoint blockage therapy. The results showed that PD1-Imi Exo had a vesicular round shape (approximately 139 nm), revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell, and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice. The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8+ T cell with cancer cell, displaying a PD1/PDL1 immune checkpoint blockage effect, and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell, exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8+ T cell. In conclusion, the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy. This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy, preventing tumor recurrence or metastasis after surgery by rebuilding the patients' immunity, thus consolidating the overall prognosis.

Abstract Background The role of stress hyperglycemia ratio (SHR) on the prognosis of spontaneous intracerebral hemorrhage (ICH) in patients with different diabetic status has not been elucidated. This study aimed to evaluate the prognostic value of SHR and admission blood glucose (ABG) for the short- and long-term mortality in diabetic and nondiabetic populations with ICH. Method Participants with ICH were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC-IV). The primary outcome was all-cause 30-day and 1-year mortality. The association of SHR and ABG with the primary outcomes in diabetic and nondiabetic cohorts were assessed by Cox proportional hazard regression. Results Overall, 1029 patients with a median age of 71.09 (IQR: 60.05–81.97) were included. Among them, 548 (53%) individuals were male, and 95 (19%) as well as 323 (31%) ones experienced the 30-day and 1-year mortality, respectively. After adjusting for confounding variables, individuals in quintile 5 of SHR had significantly higher risk of the 30-day and 1-year mortality than those in quintile 1 in the whole cohort (30-day mortality: HR 3.33, 95%CI 2.01–5.51; 1-year mortality: HR 2.09, 95% CI 1.46-3.00) and in nondiabetic patients (30-day mortality: HR 4.55, 95%CI 2.33–8.88; 1-year mortality: HR 3.06, 95%CI 1.93–4.86), but no significant difference was observed in diabetic patients. Similar results were observed for ABG as a categorical variable. As continuous variable, SHR was independently correlated with the 30-day and 1-year mortality in both of the diabetic and nondiabetic cohorts (30-day mortality: HR 2.63, 95%CI 1.50–4.60. 1-year mortality: HR 2.12, 95%CI 1.33–3.39), but this correlation was only observed in nondiabetic cohort for ABG (HR 1.00, 95%CI 0.99–1.01 for both of the 30-day and 1-year mortality). Moreover, compared with ABG, SHR can better improve the C-statistics of the original models regarding the 30-day and 1-year outcomes, especially in patients with diabetes (p

To achieve higher enthalpy and pressure, the technique of variable cross-section drive is effectively combined with the heating of light gas to enhance the intensity of the incident shock wave. A study was conducted to predict the impact of variable cross-sections on the performance of high-temperature shock tube flow using a shock tube with a 2.6:1 diameter ratio between the driver and driven sections. The driver section was filled with a helium–argon gas mixture (mass ratio of 1:9), while the driven section contained dry air. Under total pressure conditions of 14.5 MPa and total temperature of 3404 K, as well as total pressure of 45 MPa and total temperature of 4845 K in the driver section, corresponding to driven section pressures of 10 kPa and 80 kPa, the results of chemical non-equilibrium numerical simulations were compared to experimental measurements of the incident shock Mach number and total pressure. The results indicated the following: First, after adding the contraction–expansion nozzle, the incident shock accelerated through the contraction section and reflected within the contraction section. Strong oscillations occurred during the flow, with increasing intensity as the throat size decreased. Second, without the nozzle, the shock velocity increased and then decreased. However, with the nozzle, the Mach number was highest near the nozzle exit and gradually decreased thereafter. Third, the presence of the nozzle led to the formation of a distinct fan-shaped wavefront, accompanied by significant variations in flow variables such as pressure, temperature, and Mach number in the region. This phenomenon was attributed to the interaction between the shock wave and the nozzle geometry, which altered the flow dynamics. Finally, as the throat size decreased, the intensity of the incident shock also decreased. After reflecting at the end of the shock tube, the total pressure in the driven section also decreased. The numerical simulations employed a multi-component, multi-temperature chemical non-equilibrium model, validated against experimental data, to accurately capture the complex flow behavior and wave interactions within the shock tube.

The evolution of industrial land layout is a significant feature of changes in urban land use types during rapid urbanization. However, the theoretical studies investigating the evolution mechanism behind industrial land are scarce. This study developed a dynamic theoretical framework examining the relationship between government and market forces. Furthermore, this study examined the determinants of industrial land evolution in Xi’an from 1994 to 2019 by using a logistic regression model. The results showed that industrial land area increased from 55.02 km2 to 126.63 km2 from 1994 to 2013 but later rapidly reduced to 106.61 km2 in 2019. The spatial distribution of industrial land exhibited significant deindustrialization and suburbanization during park-orientated agglomeration and showed a shift from large-area small-patch to multi-center large-patch agglomeration. Factors such as development zone policies, land prices, agglomeration benefits, land supply, and transportation infrastructure are key determinants of suburbanization, while land prices and agglomeration benefits are key determinants of deindustrialization. This study reveals the mechanisms driving industrial land evolution and offers guidance in improving the rationality of urban land layout and achieving industry–city integration.

Mixed land use is recognized as a crucial strategy for enhancing urban vitality and promoting urban renewal. While existing research has mainly focused on measuring mixed land use along single dimensions, there remains a notable gap in studies that explore multidimensional measurements and their impacts at the block scale. This study introduces a multidimensional mixed-degree index based on diverse data sources such as POI and land use status to comprehensively assess mixed land use levels at the block scale in Xi’an’s central urban area. Additionally, a multiple linear regression model is applied to analyze how the built environment influences mixed land use. Findings reveal that mixed land use at the block scale can be objectively evaluated across three dimensions: quantity, distance, and attribute. In Xi’an, mixed land use demonstrates a spatial distribution characterized by core agglomeration and concentric decline. The study highlights that block area and road network density significantly influence mixed land use, with block area negatively impacting it the most and road network density positively affecting it secondarily. These insights provide valuable guidance for optimizing land use practices and promoting high-quality urban development.

Abstract Switchgrass (Panicum virgatum L.) is a prominent bioenergy crop with robust resilience to environmental stresses. However, our knowledge regarding how precipitation changes affect switchgrass photosynthesis and its responses to light and CO2 remains limited. To address this knowledge gap, we conducted a field precipitation experiment with five different treatments, including −50%, −33%, 0%, +33%, and +50% of ambient precipitation. To determine the responses of leaf photosynthesis to CO2 concentration and light, we measured leaf net photosynthesis of switchgrass under different CO2 concentrations and light levels in 2020 and 2021 for each of the five precipitation treatments. We first evaluated four light and CO2 response models (i.e., rectangular hyperbola model, nonrectangular hyperbola model, exponential model, and the modified rectangular hyperbola model) using the measurements in the ambient precipitation treatment. Based on the fitting criteria, we selected the nonrectangular hyperbola model as the optimal model and applied it to all precipitation treatments, and estimated model parameters. Overall, the model fit field measurements well for the light and CO2 response curves. Precipitation change did not influence the maximum net photosynthetic rate (Pmax) but influenced other model parameters including quantum yield (α), convexity (θ), dark respiration (Rd), light compensation point (LCP), and saturated light point (LSP). Specifically, the mean Pmax of five precipitation treatments was 17.6 μmol CO2 m−2 s−1, and the ambient treatment tended to have a higher Pmax. The +33% treatment had the highest α, and the ambient treatment had lower θ and LCP, higher Rd, and relatively lower LSP. Furthermore, precipitation significantly influenced all model parameters of CO2 response. The ambient treatment had the highest Pmax, largest α, and lowest θ, Rd, and CO2 compensation point LCP. Overall, this study improved our understanding of how switchgrass leaf photosynthesis responds to diverse environmental factors, providing valuable insights for accurately modeling switchgrass ecophysiology and productivity.

Constructing artificial ion channels is a challenging task. Herein, the de novo design of transmembrane ion channels made up of amphiphilic peptide–oligourea chimeric helices is described. They consist of an oligourea segment (7‐mer) attached to the C‐terminus of a short peptide (8‐mer). Mass spectrometry (MS) and transmission electron microscopy (TEM) analyses show that in an aqueous solution, two of these chimeras (HPU‐E and HPU‐N) independently form defined oligomeric structures. TEM also shows that they form fiber bundles. The third related chimera HPU‐F does not oligomerize (MS) but forms spherical nanostructures (TEM). HPU‐E and HPU‐N exhibit anion transport activity across lipid bilayers via antiport mechanism (HPU‐N > HPU‐E). The anion selectivity of HPU‐N is Cl−>NO3− > Br−>SCN− > I− > AcO−>F−, which can be due to anion binding within the channels rather than size exclusion. Patch‐clamp data support HPU‐N's Cl− selectivity (PCl−/PI− = 3.26). X‐ray crystal structure (1.77 Å) of HPU‐N reveals well‐packed α‐helices, and cryo‐electron microscopy data shows the formation of nanotubes (13.7 Å diameter pores) and transmembrane channels. The study shows that α‐peptide–oligourea‐based de novo design can yield unique bioactive molecules with defined structures and functions.

Lithium metal anodes (LMAs) have been considered the ultimate anode materials for next-generation batteries. However, the uncontrollable lithium dendrite growth and huge volume expansion that can occur during charge and discharge seriously hinder the practical application of LMAs. Metal–organic framework (MOF) materials, which possess the merits of huge specific surface area, excellent porosity, and flexible composition/structure tunability, have demonstrated great potential for resolving both of these issues. This article first explores the mechanism of lithium dendrite formation as described by four influential models. Subsequently, based on an in-depth understanding of these models, we propose potential strategies for utilizing MOFs and their derivatives to suppress lithium dendrite growth. We then provide a comprehensive review of research progress with respect to various applications of MOFs and their derivatives to suppress lithium dendrites and inhibit volume expansion. The paper closes with a discussion of perspectives on future modifications of MOFs and their derivatives to achieve stable and dendrite-free lithium metal batteries.

In order to realize resourceful utilization of red mud in environmentally friendly building materials, variation and mechanism of the reactivity with activated temperature were studied. Moreover, red mud geopolymer repair mortars were produced with activated red mud as main precursor, and the effect mechanism of water glass modulus and slag replacement ratio on their mechanical properties were clarified. Results show that dicalcium silicate is formed at 700 °C, the Si-O and Al-O bonds of aluminosilicate were broken and reduces in polymerization during thermal activation of red mud, resulting in an increase in activity index from 0.69 to 0.85. With water glass module increasing, mechanical properties of red mud geopolymer repair mortar ascends first and then decline, reaching the best when the module is 1.6, and further optimizes by the participation of slag. When replacement ratio of slag is 30 wt%, the compressive strength, flexural strength and interfacial bonding strength of red mud geopolymer repair mortar curing for 28 days are 58.5 MPa, 10.5 MPa, and 6.26 MPa, increase 77%, 114% and 58% comparing with the reference, respectively. After that, there is no discernible growth in the aforementioned properties. The incorporation of slag increases the integrity and denseness of the hardened red mud geopolymer at various curing ages, and thus improved its mechanical properties.

Conversion of solid waste tailings into building materials is an effective way to turn waste into resources as well as resolve the problems of their accumulation and pollution. Herein, in this paper, light-weight and high strength molybdenum tailings ceramsites (LHMCs) were prepared using molybdenum tailings as the main raw material supplemented with fly ash, sludge, steel slag and other solid wastes by egg-structure (three-layer structure) design and high-temperature sintering. The effects of raw material ratio, amount of carbon powder agent, sintering temperature, and sintering time on the properties of LHMCs were investigated, and the optimal preparation process was proposed to be preheating at 400 °C for 60 min and sintering at 1150 °C for 40 min. The results of the physicochemical properties, morphology, and component analysis of LHMCs show that the LHMCs with egg-structure including porous core, reinforced middle layer, and dense outer layer can significantly increase the strength of the ceramsites under the premise of ensuring the low density of the ceramsites. Meanwhile, the doping of molybdenum tailings improves the physical properties of the ceramsites and achieves the reuse of waste tailings. Importantly, the optimized LHMCs can meet the performance requirements of 900-grade ceramsites. This paper proposes a strategy for the preparation of tailings-doped light-weight and high-strength ceramic building materials, which provides a new idea for the recycling of solid waste.

ObjectiveThis study assessed the association between erectile dysfunction (ED) and arthritis.MethodsWeighted logistic regression and subgroup analyses were used to investigate the association between arthritis incidence and ED among participants in the 2001–2004 National Health and Nutrition Examination Survey database.ResultsAmong the participants, 27.8% and 18.5% had a self-reported history of ED and arthritis, respectively. ED was associated with arthritis (odds ratio [OR]=4.00; 95% confidence interval [CI]: 3.20–4.99; p

Despite previous attempts using multiphasic scaffolds to organize cells and bioactive elements, osteochondral repair still faces challenges, such as thin cartilage layers and uneven bone-cartilage interfaces. These issues are likely exacerbated by detrimental biochemical interactions and the formation of new blood vessels within the osteochondral unit, impacting tissue repair quality. In this study, we devised a novel freeze-welding technique to create a unified porous scaffold. Chitosan was chosen as the primary material due to its structural and compositional similarity to glycosaminoglycans in the ECM. In particular, by meticulously adjusting freezing and solute conditions, we engineered the scaffold to have an axially aligned porous structure in the cartilage layer and a radially aligned porous structure in the subchondral layer (scaffold A/R), each designed to meet the unique repair needs of the respective tissues. This scaffold showed enhanced mechanical compressibility, shape retention, and interfacial bonding capabilities. The results demonstrated that this unique spatial scaffold structure offers significant advantages over purely axial scaffolds in guiding osteochondral regeneration. These advantages were evident in its ability to independently promote cartilage and bone growth, reduce undesirable bone-cartilage crosstalk, particularly in the context of vessel invasion in the cartilage layer, and optimize the remodeling of the osteochondral interface. This study offers valuable insights into the structural design patterns for osteochondral regeneration, highlighting the potential importance of structural scaffold design in guiding endogenous tissue remodeling during heterogeneous tissue regeneration.

Abstract Northeast China, rich in natural resources and diverse biodiversity, boasts a unique habitat for threatened bird species due to its remote location and perennial cold climate. An analysis assessed the adaptability of these species using data on their geographic distribution and functional traits collected through database queries. The results revealed that threatened bird species share similar functional traits and a stronger phylogenetic signal (Blomberg mean K = 0.39) compared to common species. The Biomod2 model analyzed potentially suitable ranges and environmental drivers under current and future climate scenarios, showing a pattern of larger suitable areas in southern regions and smaller suitable areas in the north. The most critically threatened species faced greater geographical constraints (0.989), with mean annual temperature being a key influence. Altitude and water system distribution were also key factors impacting the distribution of other threatened bird species. Simulated projections under different climate scenarios (RCP 45 and 85) indicated varying degrees of expansion in the suitable range for these species. This research sheds light on the functional traits and distribution of threatened bird species in Northeast China, providing a scientific foundation for future conservation and management efforts.

Abstract Background Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. Methods We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. Results In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/β-catenin and EMT signaling pathway, and the sunitinib resistance may work through β-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. Conclusions Sunitinib resistance and Twist overexpression can activate Wnt/β-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.

Abstract Background MiRNAs are involved in the occurrence and development of many diseases. Extensive literature studies have demonstrated that miRNA-disease associations are stratified and encompass ~ 20% causal associations. Computational models that predict causal miRNA-disease associations provide effective guidance in identifying novel interpretations of disease mechanisms and potential therapeutic targets. Although several predictive models for miRNA-disease associations exist, it is still challenging to discriminate causal miRNA-disease associations from non-causal ones. Hence, there is a pressing need to develop an efficient prediction model for causal miRNA-disease association prediction. Results We developed DNI-MDCAP, an improved computational model that incorporated additional miRNA similarity metrics, deep graph embedding learning-based network imputation and semi-supervised learning framework. Through extensive predictive performance evaluation, including tenfold cross-validation and independent test, DNI-MDCAP showed excellent performance in identifying causal miRNA-disease associations, achieving an area under the receiver operating characteristic curve (AUROC) of 0.896 and 0.889, respectively. Regarding the challenge of discriminating causal miRNA-disease associations from non-causal ones, DNI-MDCAP exhibited superior predictive performance compared to existing models MDCAP and LE-MDCAP, reaching an AUROC of 0.870. Wilcoxon test also indicated significantly higher prediction scores for causal associations than for non-causal ones. Finally, the potential causal miRNA-disease associations predicted by DNI-MDCAP, exemplified by diabetic nephropathies and hsa-miR-193a, have been validated by recently published literature, further supporting the reliability of the prediction model. Conclusions DNI-MDCAP is a dedicated tool to specifically distinguish causal miRNA-disease associations with substantially improved accuracy. DNI-MDCAP is freely accessible at http://www.rnanut.net/DNIMDCAP/ .

Background: The utilization of decellularized extracellular matrix has gained considerable attention across numerous areas in regenerative research. Of particular interest is the human articular cartilage-derived extracellular matrix (hACECM), which presents as a promising facilitator for cartilage regeneration. Concurrently, the microfracture (MF) ​technique, a well-established marrow stimulation method, has proven efficacious in the repair of cartilage defects. However, as of the current literature review, no investigations have explored the potential of a combined application of hACECM and the microfracture technique in the repair of cartilage defects within a sheep model. Hypothesis: The combination of hACECM scaffold and microfracture will result in improved repair of full-thickness femoral condyle articular cartilage defects compared to the use of either technique alone. Study design: Controlled laboratory study. Methods: Full-thickness femoral condyle articular cartilage defect (diameter, 7.0 ​mm; debrided down to the subchondral bone plate) were created in the weight-bearing area of the femoral medial and lateral condyles (n ​= ​24). All of defected sheep were randomly divided into four groups: control, microfracture, hACECM scaffold, and hACECM scaffold ​+ ​microfracture. After 3, 6 and 12 months, the chondral repair was assessed for standardized (semi-) quantitative macroscopic, imaging, histological, immunohistochemical, mechanics, and biochemical analyses in each group. Result: At 3, 6 and 12 months after implantation, the gross view and pathological staining of regenerative tissues were better in the hACECM scaffold and hACECM scaffold ​+ ​microfracture groups than in the microfracture and control groups; Micro-CT result showed that the parameters about the calcified layer of cartilage and subchondral bone were better in the hACECM scaffold and hACECM scaffold ​+ ​microfracture groups than the others, and excessive subchondral bone proliferation in the microfracture group. The results demonstrate that human cartilage extracellular matrix scaffold alone is an efficient, safe and simple way to repair cartilage defects. Conclusion: hACECM scaffolds combined with/without microfracture facilitate chondral defect repair. The translational potential of this article: Preclinical large animal models represent an important adjunct and surrogate for studies on articular cartilage repair, while the sheep stifle joint reflects many key features of the human knee and are therefore optimal experimental model for future clinical application in human. In this study, we developed a human articular cartilage-derived extracellular matrix scaffold and to verify the viability of its use in sheep animal models. Clinical studies are warranted to further quantify the effects of hACECM scaffolds in similar settings.

The thermodynamic and kinetic contributions to the over-extraction of extractables by nonpolar organic solvents relative to biological lipids in exhaustive and exaggerated extractions of medical devices are studied based on the Abraham solvation model and solvent–material interactions, using low-density polyethylene (LDPE) as an exemplary material. The thermodynamic effect is evaluated by the partition constant of extractables between LDPE and extraction solvents, hexane and lipids, defined as the concentration in the polymer phase divided by the concentration in the solvent phase. The Abraham solvation model is used to correlate the measured LDPE-lipid partition constant (log10Pldpe/lipid) to construct the predictive model. Similar models are also derived from the thermodynamic cycle conversion, using the system constants of LDPE-water and Lipid-water partition systems. These constructed models, together with the predictive LDPE-hexane (log10Pldpe/hexane) model established from a previous study, are used to predict and compare the ranges and values of Pldpe/s (s = lipids and hexane) for the observed LDPE extractables over a wide hydrophobicity range in log10Po/w from zero to 30. The solvent-LDPE interactions are examined by the degree of swelling of LDPE by hexane (or other nonpolar solvents) and lipids, including the solvent diffusion rates into the material. These parameters allow the evaluation of kinetic effect on the over-extraction. The extent of over-extraction is compiled directly by experimental “overall” or “specific” migration data or indirectly calculated by the diffusion coefficient of extractables when extracted by hexane or lipids. It is concluded from this study that the extractables distribution between LDPE and lipids highly favors the lipid phase thermodynamically (Pldpe/lipid<1), and the values of Pldpe/lipid are always lower than those of Pldpe/hexane, thereby indicating that the thermodynamic effect is not the cause of over-extraction. It is the kinetic effect that dominantly contributes to the over-extraction, as supported by the material swelling and solvent diffusion rates. Finally, the extent of over-extraction has been established from a few folds to over a hundred-fold, and the median value is 7. Furthermore, the methods adopted and developed in this study can be invaluable tools in other disciplines such as the reliable prediction of extractables from other device materials and environmental sampling.

High-speed directly modulated distributed feedback (DFB) laser is crucial for high-speed optical communication systems. The modulation bandwidth and frequency chirp of such devices are primarily affected by the differential gain and linewidth enhancement factor (LEF) of the quantum wells (QWs) in the active region. In this work, the optical gain properties of long wavelength AlGaInAs-InP strained quantum wells (QWs) with different crystal orientations are numerically investigated using the multi-bands k.p theory, which considers both valence-band anisotropic and nonparabolicity. Compared to the QW laser grown on a conventional (001) substrate, a higher differential gain, and smaller LEF are observed for the laser grown on the (110) substrate with the ${\rm{(\bar{1}10)}}$ plane as the mirror facet. This is primarily due to the reduced effective mass of the valence band. The dynamic characteristics of (001)-and (110)-oriented DFB laser is theoretically studied using the one-dimensional traveling wave model (1D TWM) at ${\rm{25}}\;^\circ \text{C}$ and ${\rm{95}}\;^\circ \text{C}$. The simulation results show that the lower chirp and wider modulation bandwidth can be achieved for the QW laser grown on (110) substrate.

Abstract The FtsEX complex regulates, directly or via a protein mediator depending on bacterial genera, peptidoglycan degradation for cell division. In mycobacteria and Gram-positive bacteria, the FtsEX system directly activates peptidoglycan-hydrolases by a mechanism that remains unclear. Here we report our investigation of Mycobacterium tuberculosis FtsEX as a non-canonical regulator with high basal ATPase activity. The cryo-EM structures of the FtsEX system alone and in complex with RipC, as well as the ATP-activated state, unveil detailed information on the signal transduction mechanism, leading to the activation of RipC. Our findings indicate that RipC is recognized through a “Match and Fit” mechanism, resulting in an asymmetric rearrangement of the extracellular domains of FtsX and a unique inclined binding mode of RipC. This study provides insights into the molecular mechanisms of FtsEX and RipC regulation in the context of a critical human pathogen, guiding the design of drugs targeting peptidoglycan remodeling.

Tobacco (Nicotiana tabacum) is a globally cultivated crop, with its quality closely associated with the color and chemical composition of cured tobacco leaves. In this experiment, the effects of spraying exogenous 2, 4-epibrassinolide (EBR) and melatonin (MT) on the development of tobacco leaves at maturity stage and the quality after curing were investigated. Both EBR and MT treatments significantly enhanced the appearance quality of tobacco leaves at the stem-drying stage. Following preharvest applications, the sugar-to-alkali ratio and potassium content increased, while the contents of starch, total alkaloids, and proteins decreased. The levels of conventional chemical components were improved, enhancing the overall coordination of the tobacco. Transcriptome analysis revealed that EBR treatment down-regulated the chlorophyll biosynthetic genes hemA, MgPEC, and ChlD, while up-regulating the chlorophyll degradation genes CHL2, SGR, and PAOs. Similarly, MT treatment down-regulated the chlorophyll biosynthetic genes FC2 and MgPEC and up-regulated the degradation genes CHL2 and SGR, thus promoting chlorophyll degradation. Furthermore, in the downstream carotenoid biosynthetic pathway, both EBR and MT treatments regulated abscisic acid-related genes, with NCEDs being up-regulated and CYP707A1s down-regulated, thereby promoting the leaf ripening. Metabolomics analysis indicated that EBR treatment primarily regulated alkaloids, terpenoids, and flavonoids, while MT treatment mainly affected flavonoids. Both treatments also reduced the accumulation of the harmful substance aristolochic acid B. Comprehensive evaluations of appearance quality, physiological parameters, transcriptome, and metabolomics analyses demonstrated that exogenous spraying of EBR and MT treatments improved the maturity and quality of cured tobacco leaves, with EBR treatment exhibiting a greater effect than MT treatment.

Wildfires occur frequently in various regions of the world, causing serious damage to natural and human resources. Traditional wildfire prevention and management methods are often hampered by monitoring challenges and low efficiency. Digital twin technology, as a highly integrated virtual simulation model, shows great potential in wildfire management and prevention. At the same time, the virtual–reality combination of digital twin technology can provide new solutions for wildfire management. This paper summarizes the key technologies required to establish a wildfire digital twin system, focusing on the technical requirements and research progress in fire detection, simulation, and prediction. This paper also proposes the wildfire digital twin (WFDT) model, which integrates real-time data and computational simulations to replicate and predict wildfire behavior. The synthesis of these techniques within the framework of a digital twin offers a comprehensive approach to wildfire management, providing critical insights for decision-makers to mitigate risks and improve emergency response strategies.

Although advanced deep learning techniques have significantly improved SAR ship detection, accurately detecting small ships remains challenging due to their limited size and the few appearance and geometric clues available. In order to solve this problem, we propose several small object detection strategies. The backbone network uses space-to-depth convolution to replace stride and pooling. It reduces information loss during down-sampling. The neck integrates multiple layers of features globally and injects global and local information into different levels. It avoids the inherent information loss of traditional feature pyramid networks and strengthens the information fusion ability without significantly increasing latency. The proposed intersection-of-union considers the center distance and scale of small ships specifically. It reduces the sensitivity of intersection-of-union to positional deviations of small ships, which is helpful for training toward small ships. During training, the smaller the localization loss of small ships, the greater their localization loss gains are. By this, the supervision of small ships is strengthened in the loss function, which can make the losses more biased toward small ships. A series of experiments are conducted on two commonly used datasets, SSDD and SAR-Ship-Dataset. The experimental results show that the proposed method can detect small ships successfully and thus improve the overall performance of detectors.

Articular cartilage (AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis (OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intra-articular drug delivery systems (DDSs) in the future.

Abstract Based on the mining conditions of shallow close coal seams in the Jurassic coalfield of northern Shaanxi, in order to explore the evolution and development height prediction of water-conducting fracture zone (WCFZ), combining with measured statistical analysis, physical simulation, numerical calculation, and theoretical analysis, the evolution of mining-induced fractures and the development characteristics of WCFZ are analyzed, and the development height predicting method of WCFZ in shallow close coal seams mining is proposed. The results show that in shallow single coal seam mining, during the stage of incritical mining, the height of the WCFZ increases in a “jumping” pattern with the main roof periodic caving. After critical mining, it is basically stable. Its development height is positively correlated with the mining height. The ratio of development height to mining height is generally 20–30, and the change is not significant with the mining height, overall, the distribution of the WCFZ is “saddle shaped”. Based on close distance coal seams repeated mining, the primary fractures act as activation development when the interburden broken completely, the development of WCFZ at the mining boundary is significantly intensified, and ratio of the height to mining height in repeated mining is obviously lower than that in single seam mining, which is generally 18–25. The traditional empirical formula cannot be applied to the development prediction in shallow close coal seams mining, with an error of 10–50%. Considering the mining height, interburden thickness, and roof caving characteristics, the development height predicting method of WCFZ in shallow close coal seams mining is proposed. Compared with measured results, the calculation error is basically within 15%, which has good prediction accuracy, The research results can provide a theoretical basis for predicting the height of WCFZ in shallow close coal seams mining in the Jurassic coalfield of northern Shaanxi.