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OBJECTIVE: The study aims to evaluate tirzepatide's efficacy and safety in treating type 2 diabetes by meta-analysis and trial-sequential-analysis (TSA). MATERIALS AND METHODS: Eight databases were searched for clinical trials on tirzepatide for type 2 diabetes with a time limit of November 2022. Revman5.3 and TSA 0.9.5.10 Beta were selected for meta-analysis and TSA. RESULTS: Compared with placebo, the meta-analysis demonstrated that tirzepatide 15 mg reduced hemoglobin-type-A1C (HbA1c) (p<0.00001), fasting-serum-glucose (FSG) (p<0.00001), and weight (p<0.00001). Compared with insulin, tirzepatide 15 mg reduced HbA1c (p<0.00001), FSG (p<0.00007), and weight (p<0.00001). Compared with glucagon-like-peptide-1 receptor-agonist (GLP-1 RA), tirzepatide 15 mg reduced HbA1c (p=0.00004), FSG (p=0.001), and weight (p<0.00001). In safety endpoints, the meta-analysis revealed that adverse events (AEs) of placebo, insulin and GLP-1 RA were comparable to tirzepatide 15 mg. The total AEs (p=0.02) and gastrointestinal (GI) AEs (p=0.03) were higher in tirzepatide 15 mg than in the placebo, while hypoglycemia (<54 mg/dl) was comparable. The major adverse cardiovascular events-4 (MACE-4) (p=0.03) and hypoglycemia (<54 mg/dl) (p<0.00001) of tirzepatide 15 mg were lower when compared to insulin, while total AEs (p=0.03) were increased. Compared with GLP-1 RA, tirzepatide 15 mg was comparable in safety endpoints in total AEs and GI AEs, while hypoglycemia (<54 mg/dl) (p=0.04) was higher. TSA indicated that HgA1c, FSG, and weight benefits were conclusive. In safety endpoints, only MACE-4 and hypoglycemia (<54 mg/dl) of Tirzepatide 15 mg vs. I nsulin w ere c onclusive. H arbord regression of AEs suggested no evident publication bias (p=0.618). CONCLUSIONS: Tirzepatide 15 mg reduced HbA1c and weight more effectively than placebo, insulin, and GLP-1 RA. Total AEs were higher than placebo and insulin but comparable to GLP-1 RA. Tirzepatide 15 mg is a kind of optimal strategy to treat type 2 diabetes. However, there is a need to focus on GI AEs. [ABSTRACT FROM AUTHOR]

Abstract Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.

Abstract Alpha-fetoprotein (AFP) elevation is a well-known biomarker in various diseases, particularly in the diagnosis of hepatocellular carcinoma (HCC). Intracellular AFP has been previously implicated in promoting tumorigenesis. In this study, we discovered that AFP enhances the stability of oncoproteins c-MYC and c-MET, thereby facilitating the progression of liver and gastric tumors. Our findings suggest that AFP acts by stabilizing these oncoproteins, which are clients of heat shock protein 90 (HSP90), and prevents their degradation through ubiquitination. Intriguingly, we identified AFP as a novel co-chaperone of HSP90, demonstrating its ability to regulate the stabilization of HSP90 client proteins. Furthermore, our results indicate that inhibiting AFP or HSP90 enhances the cytotoxicity of chemotherapeutic agents in AFP-producing HCC and gastric cancer cells. These findings have significant implications for the development of therapeutic strategies targeting AFP-producing tumors, as the AFP-HSP90-mediated activation of c-MYC and c-MET provides new insights into potential treatment approaches. In summary, this study sheds light on the role of AFP in promoting tumor progression by stabilizing oncoproteins through its interaction with HSP90. The identification of this mechanism opens up new avenues for therapeutic interventions in AFP-producing tumors.

Balancing the hardness and electrical conductivity of copper alloys within complex compositions and processes poses a formidable challenge. This study proposes a strategy combining machine learning with the Pareto front techniques to identify optimal combinations of composition and processing for Cu-xTi (1.5 ≤ x ≤ 5.4, in wt.%) alloys. Through thermodynamic calculations, precipitation simulations, and experimental characterizations, the microstructural evolution of β'-Cu4Ti precipitates in the designed alloys was explored. The interpretability and predictability of the machine learning model played a crucial role in understanding impact of complex alloy compositions and processing on the evolution of properties, thereby guiding the design of Cu-Ti alloys towards improved attributes.

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is associated with a high rate of mortality and morbidity. Evidence has shown that sex differences may be an important contributor to phenotypic heterogeneity in patients with HFrEF. Although diabetes mellitus (DM) frequently coexists with HFrEF and results in a worse prognosis, there remains a need to identify sex-related differences in the characteristics and outcomes of this population. In this study, we aimed to investigate the between-sex differences in clinical profile, left ventricular (LV) remodeling, and cardiovascular risk factors and outcomes in patients with HFrEF concomitant with DM. Methods A total of 273 patients with HFrEF concomitant with DM who underwent cardiac MRI were included in this study. Clinical characteristics, LV remodeling as assessed by cardiac MRI, and cardiovascular risk factors and outcomes were compared between sexes. Results Women were older, leaner and prone to have anemia and hypoproteinemia but less likely to have ischemic etiology. Cardiac MRI revealed that despite similar LVEFs between the sexes, there was more LV concentric remodeling, less impaired global systolic peak strain in longitudinal and circumferential components and a decreased likelihood of late gadolinium enhancement presence in women than in men. During a median follow-up time of 34.6 months, women exhibited better overall survival than men did (log-rank P = 0.042). Multivariable Cox proportional hazards analysis indicated different risk factors for predicting outcomes between sexes, with hypertension [hazard ratio (HR) = 2.05, 95% confidence interval (CI) 1.05 to 4.85, P = 0.041] and hypoproteinemia (HR = 2.27, 95% CI 1.06 to 4.37, P = 0.039) serving as independent determinants of outcomes in women, whereas ischemic etiology (HR = 1.96, 95% CI 1.11 to 3.48, P = 0.021) and atrial fibrillation (HR = 1.86, 95% CI 1.02 to 3.41, P = 0.044) served as independent determinants of outcomes in men. Conclusions Among patients with HFrEF concomitant with DM, women displayed different LV remodeling and risk factors and had better survival than men did. Sex-based phenotypic heterogeneity in patients with HFrEF in the context of DM should be addressed in clinical practice.

Abstract Rainbow trapping, observed in elastic waves, has attracted considerable scientific interest owing to its potential applications in energy harvesting, buffering, and wavelength-division multiplexing devices. However, previous approaches have often necessitated complex geometric modifications to the scatterer, such as altering dimensions or shifting along diagonals to corners, limiting practical utility. Here, we realize the coupled topological edge states (CTESs) of elastic waves in a two-dimensional (2D) solid phononic crystal (PC) with inversion center changes. Changing the inversion center along the x or y directions by a specific distance can induce the topological phase transition. The topological edge states (TESs) arise at the interface by combining PCs with different topologies positioned adjacent to each other. Furthermore, it is demonstrated that TES exhibits topological robustness against defects. By introducing a gradient into the PC structure by altering the geometrical parameters of scatterers along the interface, the topological rainbow trapping of elastic waves is achieved. Finally, the CTES are generated by the interaction between TESs of different interfaces, which can lead to coupled topological rainbow trapping in phononic heterostructures with different displacement parameters along the multiple interface gradient. Our results pave the way for manipulating the symmetric and antisymmetric topological modes of elastic waves in topologically coupled waveguides, which offers potential applications in selective filtering and multiband waveguiding.

Abstract Objectives This study investigated the effectiveness of a deep convolutional neural network (CNN) in diagnosing and staging caries lesions in quantitative light-induced fluorescence (QLF) images taken by a self-manufactured handheld device. Methods A small toothbrush-like device consisting of a 400 nm UV light-emitting lamp with a 470 nm filter was manufactured for intraoral imaging. A total of 133 cases with 9,478 QLF images of teeth were included for caries lesion evaluation using a CNN model. The database was divided into development, validation, and testing cohorts at a 7:2:1 ratio. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated for model performance. Results The overall caries prevalence was 19.59%. The CNN model achieved an AUC of 0.88, an accuracy of 0.88, a specificity of 0.94, and a sensitivity of 0.64 in the validation cohort. They achieved an overall accuracy of 0.92, a sensitivity of 0.95 and a specificity of 0.55 in the testing cohort. The model can distinguish different stages of caries well, with the best performance in detecting deep caries followed by intermediate and superficial lesions. Conclusions Caries lesions have typical characteristics in QLF images and can be detected by CNNs. A QLF-based device with CNNs can assist in caries screening in the clinic or at home. Trial registration The clinical trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR2300073487, Date: 12/07/2023).

Abstract The development and utilization of bulk resources provide the basic material needs for industrial systems. However, most current resource utilization patterns are unsustainable, with low efficiencies and high carbon emissions. Here, we report a quantitative tool for resource-based industries to facilitate sustainable and low-carbon transitions within the regional economy. To evaluate the effectiveness of this tool, the saline Qinghai Lake region was chosen as a case study. After optimizing the industrial structure, the benefits of economic output, resource efficiency, energy consumption, solid waste reduction, and carbon emission reduction can be obtained. The scenario analyses exhibit disparities in different transition paths, where the carbon mitigation, economic output, and resource efficiency that benefit from optimal development paths are significantly better than those of the traditional path, indicating the urgency of adopting cleaner technology and industrial symbiosis for regional industries.

Abstract Background Glycemic control, as measured by glycosylated hemoglobin (HbA1c), is an important biomarker to evaluate diabetes severity and is believed to be associated with heart failure development. Type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) commonly coexist, and the combination of these two diseases indicates a considerably poorer outcome than either disease alone. Therefore, glycemic control should be carefully managed. The present study aimed to explore the association between glycemic control and clinical outcomes, and to determine the optimal glycemic target in this specific population. Methods A total of 262 patients who underwent cardiac MRI were included and were split by HbA1c levels [HbA1c 7.5% (poor control)]. The biventricular volume and function, as well as left ventricular (LV) systolic strains in patients in different HbA1c categories, were measured and compared. The primary and secondary outcomes were recorded. The association of different HbA1c levels with adverse outcomes was assessed. Results Despite similar biventricular ejection fractions, both patients with intensive and poor glycemic control exhibited prominent deterioration of LV systolic strain in the longitudinal component (P = 0.004). After a median follow-up of 35.0 months, 55 patients (21.0%) experienced at least one confirmed endpoint event. Cox multivariable analysis indicated that both patients in the lowest and highest HbA1c categories exhibited a more than 2-fold increase in the risk for primary outcomes [HbA1c 7.5%: HR = 2.24, 95% CI = 1.01–4.99; P = 0.038] and secondary outcomes (HbA1c 7.5%: HR = 2.65, 95% CI = 1.08–6.50; P = 0.038) compared with those in the middle HbA1c category. Conclusions We showed a U-shaped association of glycemic control with clinical outcomes in patients with T2DM and HFrEF, with the lowest risk of adverse outcomes among patients with modest glycemic control. HbA1c between 6.5% and 7.5% may be served as the optimal hypoglycemic target in this specific population.

Abstract Purpose To gain an in-depth and comprehensive understanding of Chinese organ transplant recipients’ perceptions, expectations, and suggestions of pharmacy services to hospital pharmacists. Methods This qualitative study was conducted in central China, from February to December 2020. Participants were collected with a purposive and snowball sampling method. Focus group discussions were conducted with organ transplant recipients and content analysis was applied to identify themes and subthemes. Results 21 recipients participated in the qualitative study. Four themes and thirteen subthemes were identified: (1) perceptions of clinical pharmacists and pharmacy services; (2) expectations for pharmacy service content; (3) expectations for pharmacy service form; and (4) difficulties as a special group. Conclusion The pharmacy services provided by Chinese healthcare institutions are inadequate to meet the needs of organ transplant recipients. However, the acceptance and expectation of pharmacy services by transplant recipients are high. Therefore, China should learn from the experience of developed countries and focus on the actual needs of patients to establish a better pharmacy service system for organ transplantation.

Background Plasma volume (PV) calculated from hematocrit and body weight has applications in cardiovascular disease. The current study investigated the validity of the calculated PV for predicting volume overload and its prognostic utility in patients undergoing hemodialysis (HD).Patients and methods Fifty-four HD patients were prospectively enrolled, and their actual PV (aPV) and relative PV status (PVS) were calculated. Bioelectrical impedance analysis (BIA) with assessment of and total body water (TBW), intracellular water (ICW), extracellular water (ECW), and overhydration (OH) and routine blood examinations were performed before dialysis. A second cohort of 164 HD patients was retrospectively enrolled to evaluate the relationship between the calculated PVS and the outcome, with an endpoint of all-cause mortality.Results aPV was significantly associated with TBW, ICW, ECW, OH, and ECW/TBW (all p 8.72% was significantly associated with an increased incidence of all-cause mortality (HR = 2.48, p = 0.0023).Conclusions aPV was most strongly associated with ECW measured using BIA. HD patients with higher time-averaged PVS had a higher rate of all-cause mortality.

Abstract The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase–AMP complex and the ligase–AMP–DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase–AMP complex that persist in the ligase–AMP–DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments.

AimsPrimary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing’s syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD.MethodsDatabases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles.ResultsA total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period.ConclusionsFor young patients with Cushing’s syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023416988.

Summary: The development of osteoarthritis (OA) involves subchondral bone lesions, but the role of osteoblastic autophagy-related genes (ARGs) in osteoarthritis is unclear. Through integrated analysis of single-cell dataset, Bulk RNA dataset, and 367 ARGs extracted from GeneCards, 40 ARGs were found. By employing multiple machine learning algorithms and PPI networks, three key genes (DDIT3, JUN, and VEGFA) were identified. Then the RF model constructed from these genes indicated great potential as a diagnostic tool. Furthermore, the model’s effectiveness in predicting OA has been confirmed through external validation datasets. Moreover, the expression of ARGs was examined in osteoblasts subject to excessive mechanical stress, human and mouse tissues. Finally, the role of ARGs in OA was confirmed through co-culturing explants and osteoblasts. Thus, osteoblastic ARGs could be crucial in OA development, providing potential diagnostic and treatment strategies.

Colon cancer ranks among the most prevalent malignancies worldwide, trailing only lung and breast cancer in incidence. Despite the availability of numerous therapeutic strategies, the burden of new cases and fatalities remains high in countries undergoing socioeconomic transitions. Natural products offer promising avenues for developing more effective and less toxic anticancer agents, expanding the clinical arsenal. In this investigation, we isolated a triterpenoid, (21 S,23 R,24 R)-21,23-epoxy-24-hydroxy-21-methoxytirucalla-7,25-dien-3-one (EHMT), from the fruits of Melia azedarach L., which exhibited significant inhibitory activity against colon cancer cells while sparing normal cells. EHMT effectively curtailed colony formation and induced apoptosis and cell cycle arrest in the HCT116 cell line. Furthermore, EHMT prompted the generation of reactive oxygen species (ROS) and the depolarization of mitochondrial membrane potential. Notably, EHMT treatment triggered ROS-mediated cell apoptosis via activation of the JNK signaling pathway in HCT116 cells. Additionally, our findings extended to Caenorhabditis elegans, where EHMT induced ROS accumulation and apoptosis. Collectively, these findings position EHMT as a promising candidate for the development of anticancer agents in the treatment of colon cancer, offering new hope in the battle against this formidable disease.

Semantic folding theory (SFT) is an emerging cognitive science theory that aims to explain how the human brain processes and organizes semantic information. The distribution of text into semantic grids is key to SFT. We propose a sentence-level semantic division baseline with 100 grids (SSDB-100), the only dataset we are currently aware of that performs a relevant validation of the sentence-level SFT algorithm, to evaluate the validity of text distribution in semantic grids and divide it using classical division algorithms on SSDB-100. In this article, we describe the construction of SSDB-100. First, a semantic division questionnaire with broad coverage was generated by limiting the uncertainty range of the topics and corpus. Subsequently, through an expert survey, 11 human experts provided feedback. Finally, we analyzed and processed the feedback; the average consistency index for the used feedback was 0.856 after eliminating the invalid feedback. SSDB-100 has 100 semantic grids with clear distinctions between the grids, allowing the dataset to be extended using semantic methods.

Abstract Background Sarcopenia is frequently found in patients with heart failure with reduced ejection fraction (HFrEF) and is associated with reduced exercise capacity, poor quality of life and adverse outcomes. Recent evidence suggests that axial thoracic skeletal muscle size could be used as a surrogate to assess sarcopenia in HFrEF. Since diabetes mellitus (DM) is one of the most common comorbidities with HFrEF, we aimed to explore the potential association of axial thoracic skeletal muscle size with left ventricular (LV) remodeling and determine its prognostic significance in this condition. Methods A total of 243 diabetes patients with HFrEF were included in this study. Bilateral axial thoracic skeletal muscle size was obtained using cardiac MRI. Patients were stratified by the tertiles of axial thoracic skeletal muscle index (SMI). LV structural and functional indices, as well as amino-terminal pro-B-type natriuretic peptide (NT-proBNP), were measured. The determinants of elevated NT-proBNP were assessed using linear regression analysis. The associations between thoracic SMI and clinical outcomes were assessed using a multivariable Cox proportional hazards model. Results Patients in the lowest tertile of thoracic SMI displayed a deterioration in LV systolic strain in three components, together with an increase in LV mass and a heavier burden of myocardial fibrosis (all P

Objective: Osteoarthritis (OA), which involves total joint damage and dysfunction, is a leading cause of disability worldwide. However, its exact pathogenesis remains unclear. Here, we identified TCF12 as an important regulator of the progression of OA. Methods: qRT-PCR, immunoblotting and immunohistochemistry (IHC) were used to detect the expression level of TCF12. The interaction of TCF12 with its downstream factor CXCR4 was assessed by Western blotting, immunofluorescence, qRT-PCR and luciferase assays. A mouse model was generated to examine the functions and mechanism of TCF12 in vivo. Result: TCF12 expression was upregulated in chondrocytes stimulated with IL-1β and osteoarthritic chondrocytes. TCF12 upregulates the expression of CXCR4 and leads to dysfunction of the TGF-β signaling pathway. Furthermore, knockdown of TCF12 alleviated cartilage damage in a mouse model generated by destabilization of the medial meniscus (DMM). Conclusion: TCF12 aggravates the progression of OA by targeting CXCR4 and then activating the TGF-β signaling pathway, suggesting that TCF12 may be a new target for the treatment of OA. The translational potential of this article: Transcription Factor 12(TCF12), is known to regulate cell development and differentiation, It has been widely studied in various organs and diseases, but its role in OA remains unclear. Here, we identified Transcription Factor 12(TCF12) as an important regulator mediating chondrocyte senescence and cartilage extracellular matrix degradation indicating its role in OA. We found that TCF12 expression was upregulated both locally and systemically as OA advanced in patients with OA, and in mice after DMM surgery to induce OA. TCF12 expression caused striking progressive articular cartilage damage, synovial hyperplasia in OA mice, and remarkably, it was relieved by intra-articular administration of mutant mouse TCF12 lentiviral vector (shTCF12). Furthermore, TCF12 upregulated the expression of CXCR4, leading to exacerbation of experimental OA partially through activation of TGF-β signaling in chondrocytes. TCF12 expression was upregulated in chondrocytes treated with IL-1β and osteoarthritic chondrocytes. Our findings established an essential role of TCF12 in chondrocyte senescence and cartilage extracellular matrix degradation during OA, and identified intra-articular injection of TCF12 as a potential therapeutic strategy for OA prevention and treatment.

Abstract Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart. It typically occurs following cardiac injuries or diseases. However, the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis. The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis, providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms. Furthermore, reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis. In this review, we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms, drug discovery as well as therapy method.

Abstract Background Gadolinium-enhanced cardiovascular magnetic resonance (CMR) is the most widely used approach for diagnosing myocardial fibrosis with late gadolinium enhancement (LGE) in cardiomyopathy associated with Duchenne muscular dystrophy. Given the limitations and safety of gadolinium use, we wanted to develop and evaluate multi-parametric pre-contrast CMR models for the diagnosis of LGE and investigate whether they could be utilised as surrogates for LGE in DMD patients. Methods A total of 136 DMD patients were prospectively recruited and separated into LGE − and LGE + groups. In the first subset of patients (derivation cohort), regression models for the diagnosis of LGE were built by logistic regression using pre-contrast sequence parameters. In a validation cohort of other patients, the models’ performances were evaluated. Results EF, native T1 and longitudinal strain alone, as well as their combinations form seven models. The model that included EF, native T1 and longitudinal strain had the best diagnostic value, but there was no significant difference in diagnostic accuracy among the other models except EF. In the validation cohort, the diagnosis outcomes of models were moderate consistent with the existence of LGE. The longitudinal strain outperformed the other models in terms of diagnostic value (sensitivity: 83.33%, specificity: 54.55%). Conclusions Pre-contrast sequences have a moderate predictive value for LGE. Thus, pre-contrast parameters may be considered only in a specific subset of DMD patients who cannot cooperate for long-time examinations and have contradiction of contrast agent to help predict the presence of LGE. Trial registration number (TRN) ChiCTR1800018340 Date of registration 20180107

Large-depth and multiscale gradient microstructure in dual-phase Al0.6CoCrFeNi high entropy alloy (HEA) were fabricated by explosion hardening (EH) technique. The gradient microstructure evolution was investigated in detail. The microhardness distribution and tensile properties near EH affected surface were also determined. The formation and strengthening mechanisms of gradient microstructure after EH treatment were subsequently analyzed. Experimental results showed that the multiscale gradient microstructure in terms of grain size, phase morphology, dislocation structure, texture was induced in dual-phase (BCC + FCC) HEA by EH technique. The closer to EH affected surface, the finer grain size, higher dislocation density and stronger texture intensity. The deformation and break of spinodal decomposition and formation of new grain boundaries by dislocation structure contributed to grain refinement and transition of equiaxed grains to dendritic grains from lower area to EH affected surface. After EH treatment, the microhardness generally increased with a maximum increase of ∼67% within 5 mm from EH affected surface, the tensile yield stress increased from 320 MPa to maximum of 700 MPa. The strengthening mechanism is different at various depth positions: near EH affected surface, the main strengthening mechanism is high-density dislocations, stacking faults and grain refinement; in areas relatively far from EH affected surface, only dislocation structure contributed to the strengthening of mechanical properties.

Fenpropathrin (Fen), a volatile pyrethroid insecticide, is used widely for agricultural applications and has been reported to increase the risk of Parkinson’s disease (PD). However, the molecular basis, underlying mechanisms, and pathophysiology of Fen-exposed Parkinsonism remain unknown. Recent studies have revealed epigenetic mechanisms underlying PD-related pathway regulation, including DNA methylation. Epigenetic mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. After whole-genome bisulfite sequencing (WGBS) of midbrain tissues from a Fen-exposed PD-like mouse model, we performed an association analysis of DNA methylation and gene expression. Then we successfully screened for the DNA methylation differential gene Ambra1, which is closely related to PD. The hypermethylation-low expression Ambra1 gene aggravated DA neuron damage in vitro and in vivo through the Ambra1/Parkin/LC3B-mediated mitophagy pathway. We administered 5-aza-2′-deoxycytidine (5-Aza-dC) to upregulate Ambra1 expression, thereby reducing Ambra1-mediated mitophagy and protecting DA neurons against Fen-induced damage. In conclusion, these findings elucidate the potential function of Ambra1 under the regulation of DNA methylation, suggesting that the inhibition of DNA methylation may alleviate Fen-exposed neuron damage.

The coronavirus disease 2019 (COVID-19) pandemic caused by frequently mutating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a worldwide impact. However, detailed data on the potential aerosol transmission of SARS-CoV-2 in real-world and controlled laboratory settings remain sparse. During the COVID-19 pandemic in Shanghai, China in 2022, samples were collected in a Fangcang shelter hospital, a large-scale temporary hospital rapidly built by converting the existing National Exhibition and Convention Center (Shanghai) into a health care facility. Aerosol samples at different sites and intervals around patients and in public areas, surface samples, and pharyngeal swab samples from corresponding patients were included. Samples were tested for SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR) assays, followed by sequencing if the cycle threshold (Ct) value was < 30. The positivity rate for SARS-CoV-2 in aerosol samples was high in contaminated zones (37.5%, 104/277), especially around the bed (41.2%, 68/165) and near ventilation inlets (45.2%, 14/31). The prevalence of SARS-CoV-2 around the bed, public areas, and air inlets of exhaust vents fluctuated and was closely related to the positivity rate among patients at corresponding sampling sites. Some surface samples of different personal protective equipment from medical staff had high positivity rates. Sixty sequences of joined ORF1ab and spike genes obtained from sixty samples represented two main clusters of Omicron SARS-CoV-2. There was consistency in virus sequences from the same patient and their environment, and the detected virus sequences matched those of virus strains in circulation during the collection periods, which indicated a high likelihood of cross-contamination in the Fangcang shelter hospital. In summary, the results provide a quantitative and real landscape of the aerosol transmission of SARS-CoV-2 and a patient-centered view of contamination in large and enclosed spaces and offer a useful guide for taking targeted measures to avoid nosocomial infections during the management of SARS-CoV-2 or other respiratory virus diseases in a Fangcang shelter hospital.

Abstract Necrotizing enterocolitis (NEC) is a life-threatening, inflammatory disease affecting premature infants with intestinal necrosis, but the mechanism remains unclear. Neonatal macrophages are thought to play an important role in the pathogenesis of NEC through the production of proinflammatory cytokines. Restriction of cytokine expression in macrophages of NEC tissues may be beneficial. In adult macrophages, interfering with Rac1 has been shown to influence the expression of cytokines. Here, we investigated whether interfering with Rac1 in neonatal macrophages affects their inflammatory responses. First, we found that Rac1-activation was upregulated in the macrophages of rats with NEC model induction compared to controls. The M1 macrophages derived from human neonatal monocytes showed greater Rac1-activation than the M2 macrophages derived from the same monocytes. Inhibition of Rac1-activation by NSC23766 potently reduced the production of proinflammatory cytokines in these M1 macrophages. While neonatal monocytes differentiated into M1 macrophages in vitro, NSC23766 significantly altered cell function during the first six days of incubation with GM-CSF rather than during the subsequent stimulation phase. However, the same effect of NSC23766 was not observed in adult macrophages. Using mass spectrometry, Y-box binding protein 1 (YB1) was identified as being downregulated upon inhibition of Rac1-activation in the neonatal macrophages. Moreover, we found that inhibition of Rac1-activation shortens the poly A tail of PABPC1 mRNA, thereby reducing the translation of PABPC1 mRNA. Consequently, the downregulation of PABPC1 resulted in a reduced translation of YB1 mRNA. Furthermore, we found that TLR4 expression was downregulated in neonatal macrophages, while YB1 expression was reduced. Adding resatorvid (TLR4 signaling inhibitor) to the macrophages treated with NSC23766 did not further reduce the cytokine expression. These findings reveal a novel Rac1-mediated pathway to inhibit cytokine expression in neonatal M1 macrophages and suggest potential targets for the prevention or treatment of NEC.

Abstract Plague, caused by Yersinia pestis, is a zoonotic disease that can reemerge and cause outbreaks following decades of latency in natural plague foci. However, the genetic diversity and spread pattern of Y. pestis during these epidemic-silent cycles remain unclear. In this study, we analyze 356 Y. pestis genomes isolated between 1952 and 2016 in the Yunnan Rattus tanezumi plague focus, China, covering two epidemic-silent cycles. Through high-resolution genomic epidemiological analysis, we find that 96% of Y. pestis genomes belong to phylogroup 1.ORI2 and are subdivided into two sister clades (Sublineage1 and Sublineage2) characterized by different temporal-spatial distributions and genetic diversity. Most of the Sublineage1 strains are isolated from the first epidemic-silent cycle, while Sublineage2 strains are predominantly from the second cycle and revealing a west to east spread. The two sister clades evolved in parallel from a common ancestor and independently lead to two separate epidemics, confirming that the pathogen responsible for the second epidemic following the silent interval is not a descendant of the causative strain of the first epidemic. Our results provide a mechanism for defining epidemic-silent cycles in natural plague foci, which is valuable in the prevention and control of future plague outbreaks.

Abstract Background Insulin is commonly used in type 2 diabetes mellitus (T2DM) to achieve glycemic control. However, recent evidence showed that insulin use is associated with poor outcomes in the context of heart failure (HF). Since heart failure with reduced ejection fraction (HFrEF) accounts for approximately 50% of cases in the general HF population, we aimed to evaluate the effect of insulin treatment on left ventricular (LV) remodeling and contractility abnormalities in a HFrEF cohort and assess whether insulin was a predictor of adverse outcomes in this entity. Methods A total of 377 HFrEF patients who underwent cardiac MRI were included and divided according to diabetes status and the need for insulin treatment. LV structural and functional indices, as well as systolic strains, were measured. The determinants of impaired myocardial strains were assessed using linear regression analysis. The associated endpoints were determined using a multivariable Cox proportional hazards model. Results T2DM patients on insulin displayed a higher indexed LV end-diastolic volume and LV mass than those with T2DM not on insulin or those without T2DM, despite similar LV ejection fractions, accompanied by a higher three-dimensional spherical index (P

Extracting geoscientific dataset names from the literature is crucial for building a literature–data association network, which can help readers access the data quickly through the Internet. However, the existing named-entity extraction methods have low accuracy in extracting geoscientific dataset names from unstructured text because geoscientific dataset names are a complex combination of multiple elements, such as geospatial coverage, temporal coverage, scale or resolution, theme content, and version. This paper proposes a new method based on the hierarchical temporal memory (HTM) model, a brain-inspired neural network with superior performance in high-level cognitive tasks, to accurately extract geoscientific dataset names from unstructured text. First, a word-encoding method based on the Unicode values of characters for the HTM model was proposed. Then, over 12,000 dataset names were collected from geoscience data-sharing websites and encoded into binary vectors to train the HTM model. We conceived a new classifier scheme for the HTM model that decodes the predictive vector for the encoder of the next word so that the similarity of the encoders of the predictive next word and the real next word can be computed. If the similarity is greater than a specified threshold, the real next word can be regarded as part of the name, and a successive word set forms the full geoscientific dataset name. We used the trained HTM model to extract geoscientific dataset names from 100 papers. Our method achieved an F1-score of 0.727, outperforming the GPT-4- and Claude-3-based few-shot learning (FSL) method, with F1-scores of 0.698 and 0.72, respectively.

Endogenous peptides, particularly those with post-translational modifications, are increasingly being studied as biomarkers for diagnosing various diseases. However, they are weakly ionizable, have a low abundance in biological samples, and may be interfered with by high levels of proteins, peptides, and other macromolecular impurities, resulting in a high limit of detection and insufficient amounts of post-translationally modified peptides in real biological samples to be examined. Therefore, separation and enrichment are necessary before analyzing these biomarkers using mass spectrometry. Mesoporous materials have regular adjustable pores that can eliminate large proteins and impurities, and their large specific surface area can bind more target peptides, but this may result in the partial loss or destruction of target peptides during centrifugal separation. On the other hand, magnetic mesoporous materials can be used to separate the target using an external magnetic field, which improves the separation efficiency and yield. Core–shell magnetic mesoporous materials are widely utilized for peptide separation and enrichment due to their biocompatibility, efficient enrichment capability, and excellent recoverability. This paper provides a review of the latest progress in core–shell magnetic mesoporous materials for enriching glycopeptides and phosphopeptides and compares their enrichment performance with different types of functionalization methods.

Abstract Background This study aimed to examine the bidirectional relationship between social isolation and cognitive performance among Chinese middle-aged and older adults. Methods We used four waves of data from the China Health and Retirement Longitudinal Study. A latent growth model (LGM) was applied to examine the association between social isolation and cognitive performance across different characteristics. Results In the analysis, we ultimately included 9,367 participants after excluding respondents with missing key variables. Social isolation and cognitive performance showed significant differences across time. After adjusting for the confounders, there was a significant association between higher social isolation and poor cognitive performance (β = −1.38, p

In this study, graded tantalum scaffolds were manufactured by electron beam powder bed fusion (EB-PBF). Compression-compression fatigue testing was conducted on the EB-PBF built graded tantalum scaffolds. The compressive fatigue behavior and compressive fatigue strength of graded tantalum scaffolds with vertical gradient (VG) and parallel gradient (PG) states were investigated. In the fatigue testing, the failure of PG graded scaffold was concentrated on the lowest strength constituent, resulting in higher cyclic ratcheting strain and fatigue damage strain. In terms of the VG graded scaffold, due to the simultaneous uniform deformation of each structure, the strain accumulation in a single cycle was small, resulting in the low cyclic ratcheting strain. In addition, the propagation of fatigue cracks in pore structure with higher strength can be retarded by the stress redistribution, resulting in the low fatigue damage strain. Therefore, the design idea of graded pore structure under identical strain condition is beneficial to obtain porous tantalum scaffold with high compressive fatigue strength.

With the wide application of open source software, the security of open source components has become a non-negligible problem in software development. In this paper, based on the research on deep learning algorithms, the deep reinforcement learning algorithm DQN is proposed, and the DQN-LightGBM model is constructed by combining LightGBM classifiers to achieve better mining performance. This model introduces the attention mechanism and BiLSTM network, and the TextACBL vulnerability identification algorithm is proposed. In the end, the performance of the open source component vulnerability mining model is evaluated to investigate its impact on vulnerability identification, risk assessment, and dependency analysis of open source components. The results show that the performance of DQN-LightGBM model is above 0.9 in accuracy, checking accuracy, checking completeness, AUC value, and F1, and the mining completion time is only 54s, which is the best. The accuracy of TextACBL model in identifying the types of vulnerabilities is above 94%, and the vulnerability danger levels on the seven items measured are high, low, high, high, and high risk, respectively, medium risk, high risk, and medium risk. The differences in the global graph features of the identified normal and vulnerability samples are obvious, and there are frequent dependencies in the probability graphs of the opcodes of the vulnerability samples. This study allows for the assessment of security risks of open source components and the comprehensive, accurate, and efficient conduct of dependency analysis.

ObjectiveThere is a notable research gap on the mental health challenges faced by hospital pharmacists in the post-pandemic era. Therefore, the present study aims to explore mental health status, influencing factors, coping strategies, and the mediating effect of resilience of home quarantine hospital pharmacists (HQHPs).MethodsAn embedded mixed-method study was conducted in Zhengzhou, a megalopolis in central China, from 20 October to 3 November 2022. For the qualitative study, semi-structured interviews and focus group discussions were conducted among HQHPs to understand their mental health state，the factors that affect their mental health, and the alleviating strategies they used. For the quantitative study, the Generalized Anxiety Disorder Scale (GAD-7) and the Chinese version of the Connor-Davidson Resilience Scale (CD-RISC-25) were used to explore the mental health level of HQHPs. Meanwhile, the mediating effect of resilience was explored and verified with the bootstrap method or the structural equation model.Results20 HQHPs participated in the qualitative study. Two themes were identified in terms of the factors that influenced the HQHPs’ mental health levels. The positive factors include optimism, family company, and connection with friends, while the negative factors include inadequate supplies, inadequate information, and other emergencies. 210 HQHPs participated in the quantitative study, with a median resilience score of 66 [55.75, 74] in the lowest score range and an anxiety score of 5 [2, 7] in the mild anxiety range. The correlation analysis showed that nine of the 10 influencing factors identified in qualitative research were positively correlated with CD-RISC-25 scores and negatively correlated with the GAD-7 score. The mediating effect of resilience on anxiety was significant (95% bootstrap CI [−1.818, −0.384], p

Objective Self-directed learning (SDL) has been embraced by the medical community as a core professional competency, with motivation considered a crucial component of SDL. However, little is known about how hospital pharmacists perceive motivation in SDL in the workplace. This study aimed to examine the intrinsic and external motivation of hospital pharmacists in SDL.Design This study employed a multicentre qualitative design, which lasted 13 months from May 2020 to June 2021. The interviews were audiorecorded, transcribed verbatim and analysed in NVivo V.12.0. Thematic analysis method was used to analyse the data.Setting The study took place in nine public hospitals located in urban areas of Henan Province.Participants Sixteen hospital pharmacists were enrolled from the pharmacy departments of the sample hospitals, using a purposive sampling method.Results Sixteen one-on-one semistructured interviews were conducted, identifying intrinsic and extrinsic motivation in SDL for hospital pharmacists in the workplace. Intrinsic motivation includes curiosity and interest, achievement, self-efficacy and personal growth. Extrinsic motivation includes a more comprehensive set of elements, such as interpersonal motivations, work-related motivations and career-related motivations.Conclusions Personal interests, the influence of surrounding individuals (directly or indirectly), work-related requirements and pressures, and professional development requirements and pressures are the main intrinsic or extrinsic motivations for SDL among hospital pharmacists in China. Future research may focus on these aspects to enhance the SDL competence of hospital pharmacists and other medical personnel.

In recent years, there has been growing scientific interest in balancing the bioactivity and cytotoxicity of antimicrobial peptides (AMPs) for more comprehensive research and application. In this study, we focused on t-DPH1, a representative member of the dermaseptin family, as a template. We synthesized five analogues were synthesised to to assess the impact of three conserved features of the dermaseptin family (1. the tryptophan residue at 3rd position, 2. the consensus motif at mid-region, and 3. C-terminal amidation) on the bioactivity of t-DPH1 and their potential to reduce cytotoxicity. Our results demonstrated that analogues lacking an amino group at the C-terminus, specifically t-DPH1-NH2, exhibited potent antimicrobial activity against Gram-negative bacteria, including Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Furthermore, t-DPH1-NH2 retained its robust antiproliferative activity against the human non-small lung cancer cell line H157. Regarding cytotoxicity, t-DPH1-NH2 displayed lower levels of haemolytic activity and cytotoxicity against two normal cell lines. Notably, we employed C. elegans as an in vivo model to assess the cytotoxicity of peptides, and the results revealed no induction of in vivo toxicity by t-DPH1-NH2. Collectively, t-DPH1-NH2 provides valuable insights for further investigation as promising bioactive peptide templates in the development of antibiotic and anticancer prototype drugs. The modifications implemented based on the conserved structure of the peptide family offer a new direction for reducing the cytotoxicity of peptides.

ObjectiveThe relationship between serum selenium levels and papillary thyroid cancer (PTC), especially the pathological features, still remains controversial. We conducted this study to investigate the relationship between serum selenium levels and PTC in a Chinese population.MethodsCross-sectional data of 284 patients with PTC were collected from the First Affiliated Hospital of Shandong First Medical University. The general clinical characteristics, serum selenium levels, and tumor pathological features were described in PTC. The association between serum selenium levels and pathological features in PTC was analyzed using SPSS 26.0 statistical software.ResultsOur results showed that the median serum selenium level was 79.15 μg/L (IQR: 71.00 - 86.98 μg/L) in PTC patients. Serum selenium levels were lower in females than males (p = 0.035). Serum selenium levels were negatively correlated with the number of lymph node metastases (p = 0.048). High serum selenium (OR = 0.397, 95%CI: 0.217 - 0.725) and diastolic blood pressure (OR = 1.028, 95%CI: 1.005 - 1.051) were related factors for the incidence of bilateral tumors. High serum selenium (OR = 0.320, 95%CI: 0.166 - 0.617) and diastolic blood pressure (OR = 1.066, 95%CI: 1.031 - 1.103) were related factors for tumor multifocal incidence.ConclusionsThe serum selenium levels of PTC patients in females were lower than males. High serum selenium levels might be a protective factor in PTC patients. Further research is necessary to better understand the influence of selenium on PTC progression.

Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources.

Abstract Background This study presented the mortality trend of ischemic heart disease (IHD) in Chinese residents from 2010 to 2019 and provided a basis for further establishment of relevant interventions. Methods Data, such as sex, age, urban and rural areas, and death status, were extracted from the China Death Surveillance Dataset from 2010 to 2019, with mortality and age-adjusted death rates (AADRs) as the main indicators. The joinpoint regression model was used to analyze mortality and AADRs trends in IHD. A semi-structured expert interview was conducted to propose targeted intervention measures and countermeasures. Results We observed an overall upward trend in IHD mortality rates and AADRs in China from 2010 to 2019 (average annual percentage change [AAPC] = 5.14%, AAPCAADRs = 1.60%, P 0.05) mortality rates increased, with the mortality rate higher in rural areas than in urban areas. In the age analysis, mortality rate was higher in middle-aged and older adults than in other age groups. The age-sex cross-analysis found the highest trend in mortality rates among females aged ≥ 75 years (annual percentage change [APC] = 2.43%, P

Background: Nuclear receptor binding protein 1 (NRBP1) and ATP-binding cassette subfamily G member 2 (ABCG2) was the gout risk gene and high-capacity urate exporter respectively. However, the relationship between NRBP1 and ABCG2 and the underlying molecular mechanism contributing to these associations are unknown. Methods: Firstly, the efficiency of the overexpression and knockdown of NRBP1 was confirmed by western blot. Next, the effect of NRBP1 overexpression and knockdown on the expression of ABCG2, organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) was detected by qRT-PCR and western blot. At the same time, the cellular location of ABCG2 and its expression after NRBP1 overexpression and knockdown was tested by immunofluorescence (IF) staining. Then, the mechanism of NRBP1 modulates ABCG2 expression was evaluated by western blot with or without the β-catenin inhibitor (21H7). Results: The lentivirus system was used to generate stable NRBP1 overexpression, while the plasmids carrying a NRBP1 siRNA was generated to knockdown NRBP1 expression in HK-2 cells. Meanwhile, the overexpression of NRBP1 significantly decreased the mRNAs and proteins expression of GLUT9 and URAT1, while the knockdown of NRBP1 increased the mRNAs and proteins expression of ABCG2 significantly. In addition, the NRBP1 modulates the expression of ABCG2 was by ctivating the Wnt/β-catenin pathway in HK-2 cells according to the IF and western blot results. Conclusion: Taken together, our study demonstrated that NRBP1 inhibition played an essential role in attenuating hyperuricemia and gout by upregulation of ABCG2 via Wnt/β-catenin signaling pathway in HK-2 cells. Resumen: Antecedentes: La proteína de unión al receptor nuclear 1 (NRBP1) y el miembro G de la subclase ATP binding Box 2 (ABCG2) son los genes de riesgo de gota y los genes de salida de urato de alto rendimiento, respectivamente. Sin embargo, se desconoce la relación entre NRBP1 y ABCG2, y los posibles mecanismos moleculares que conducen a estas asociaciones. Métodos: En primer lugar, la sobreexpresión y el knockout de NRBP1 fueron confirmados por Western-blot. Los efectos de la sobreexpresión y knockout de NRBP1 en la expresión de ABCG2, transportador de aniones orgánicos 1 (OAT1), transportador de glucosa 9 (GLUT9) y transportador de ácido úrico 1 (URAT1) fueron detectados por qRT-PCR y Western-blot. Mientras tanto, la localización y expresión de ABCG2 después de la sobreexpresión y knockout de NRBP1 fueron detectadas por inmunofluorescencia (IF). Luego, el efecto regulador de NRBP1 sobre la expresión de ABCG2 fue estudiado por Western-blot y comparado con el inhibidor de la β-catenina (21H7). Resultados: El sistema lentiviral indujo una sobreexpresión estable de NRBP1, mientras que el plásmido portador de SiRNA NRBP1 inhibió la expresión de NRBP1 en las células HK-2. Mientras tanto, la sobreexpresión de NRBP1 redujo significativamente la expresión de ARNm y proteínas de GLUT9 y URAT1, mientras que el knockout de NRBP1 aumentó significativamente la expresión de ARNm y proteínas de ABCG2. Además, de acuerdo con los resultados de IF y Western-blot, NRBP1 regula la expresión de ABCG2 activando la vía Wnt/β-catenina en las células HK-2. Conclusión: La inhibición del NRBP1 aumenta la regulación de ABCG2 a través de la vía de señalización Wnt/β-catenina, que desempeña un papel importante en la reducción de la hiperuricemia y la gota.

Accurate three-dimensional (3D) cloud structure measurements are critical for assessing the influence of clouds on the Earth’s atmospheric system. This study extended the MODIS (Moderate-Resolution Imaging Spectroradiometer) cloud vertical profile (64 × 64 scene, about 70 km in width × 15 km in height) retrieval technique based on conditional generative adversarial networks (CGAN) to construct seamless 3D cloud fields for the MODIS granules. Firstly, the accuracy and spatial continuity of the retrievals (of 7180 samples from the validation set) were statistically evaluated. Then, according to the characteristics of the retrieval error, a spatially overlapping-scene ensemble generation method and a bidirectional ensemble binning probability fusion (CGAN-BEBPF) technique were developed, which improved the CGAN retrieval accuracy and support to construct seamless 3D clouds for the MODIS granules. The CGAN-BEBPF technique involved three steps: cloud masking, intensity scaling, and optimal value selection. It ensured adequate coverage of the low reflectivity areas while preserving the high-reflectivity cloud cores. The technique was applied to retrieve the 3D cloud fields of Typhoon Chaba and a multi-cell convective system and the results were compared with ground-based radar measurements. The cloud structures of the CGAN-BEBPF results were highly consistent with the ground-based radar observations. The CGAN-EBEPF technique retrieved weak ice clouds at the top levels that were missed by ground-based radars and filled the gaps of the ground-based radars in the lower levels. The CGAN-BEBPF was automated to retrieve 3D cloud radar reflectivity along the MODIS track over the seas to the east and south of mainland China, providing valuable cloud information to support maritime and near-shore typhoons and convection prediction for the cloud-sensitive applications in the regions.

Abstract Existing therapeutics for autoimmune diseases remain problematic due to low efficacy, severe side effects, and difficulties to reach target tissues. Herein, we design multifunctional fusion nanovesicles that can target lesions for the treatment of autoimmune skin diseases. The grapefruit‐derived exosome‐like nanovesicles (GEVs) with anti‐inflammatory and antioxidant effects are first encapsulated with CX5461, an immunosuppressant with anti‐proliferative properties to form GEV@CX5461. In order to enhance therapeutic efficiency and safety, GEV@CX5461 are then fused with CCR6+ nanovesicles derived from membranes of engineered gingiva‐derived mesenchymal stem cells (GMSCs). The resulting FV@CX5461 not only maintain the bioactivity of GEVs, CX5461, and GMSC membranes but also home to inflamed tissues rich in chemokine CCL20 through the chemotaxis function of CCR6 on FVs. Moreover, FV@CX5461 reduce the secretion of inflammatory factors, calm down Th17 cell activation, and induce Treg cell infiltration. Finally, impressive therapeutic efficiency in both psoriasis and atopic dermatitis disease models is demonstrated using FV@CX5461 to reshape the unbalanced immune microenvironment. A nanotherapeutic drug delivery strategy is developed using fusion nanovesicles derived from plant and animal cells with high clinical potential.

ABSTRACT Linker histone H1 plays a crucial role in various biological processes, including nucleosome stabilization, high-order chromatin structure organization, gene expression, and epigenetic regulation in eukaryotic cells. Unlike higher eukaryotes, little about the linker histone in Saccharomyces cerevisiae is known. Hho1 and Hmo1 are two long-standing controversial histone H1 candidates in budding yeast. In this study, we directly observed at the single-molecule level that Hmo1, but not Hho1, is involved in chromatin assembly in the yeast nucleoplasmic extracts (YNPE), which can replicate the physiological condition of the yeast nucleus. The presence of Hmo1 facilitates the assembly of nucleosomes on DNA in YNPE, as revealed by single-molecule force spectroscopy. Further single-molecule analysis showed that the lysine-rich C-terminal domain (CTD) of Hmo1 is essential for the function of chromatin compaction, while the second globular domain at the C-terminus of Hho1 impairs its ability. In addition, Hmo1, but not Hho1, forms condensates with double-stranded DNA via reversible phase separation. The phosphorylation fluctuation of Hmo1 coincides with metazoan H1 during the cell cycle. Our data suggest that Hmo1, but not Hho1, possesses some functionality similar to that of linker histone in Saccharomyces cerevisiae, even though some properties of Hmo1 differ from those of a canonical linker histone H1. Our study provides clues for the linker histone H1 in budding yeast and provides insights into the evolution and diversity of histone H1 across eukaryotes. IMPORTANCE There has been a long-standing debate regarding the identity of linker histone H1 in budding yeast. To address this issue, we utilized YNPE, which accurately replicate the physiological conditions in yeast nuclei, in combination with total internal reflection fluorescence microscopy and magnetic tweezers. Our findings demonstrated that Hmo1, rather than Hho1, is responsible for chromatin assembly in budding yeast. Additionally, we found that Hmo1 shares certain characteristics with histone H1, including phase separation and phosphorylation fluctuations throughout the cell cycle. Furthermore, we discovered that the lysine-rich domain of Hho1 is buried by its second globular domain at the C-terminus, resulting in the loss of function that is similar to histone H1. Our study provides compelling evidence to suggest that Hmo1 shares linker histone H1 function in budding yeast and contributes to our understanding of the evolution of linker histone H1 across eukaryotes.

Random Fourier features represent one of the most influential and wide-spread techniques in machine learning to scale up kernel algorithms. As the methods based on random Fourier approximation of the kernel function can overcome the shortcomings of machine learning methods that require a large number of labeled sample, it is effective to be applied to the practical areas where samples are difficult to obtain. Network traffic forwarding policy making is one such practical application, and it is widely concerned in the programmable networks. With the advantages of kernel techniques and random Fourier features, this paper proposes an application of network traffic forwarding policy making method based on random Fourier approximation of kernel function in programmable networks to realize traffic forwarding policy making to improve the security of networks. The core of the method is to map traffic forwarding features to Hilbert high-dimensional space through random Fourier transform, and then uses the principle of maximum interval to detect adversarial samples. Compared with the traditional kernel function method, it improves the algorithm efficiency from square efficiency to linear efficiency. The AUC on the data set from real-world network reached 0.9984, showing that the method proposed can realize traffic forwarding policy making effectively to improve the security of programmable networks.

Boosting is an ensemble learning method that combines a set of weak learners into a strong learner to minimize training errors. AdaBoost algorithm, as a typical boosting algorithm, transforms weak learners or predictors to strong predictors in order to solve problems of classification. With remarkable usability and effectiveness, AdaBoost algorithm has been widely used in many fields, such as face recognition, speech enhancement, natural language processing, and network intrusion detection. In the large-scale enterprise network environment, more and more companies have begun to build trustworthy networks to effectively defend against hacker attacks. However, since trustworthy networks use trusted flags to verify the legitimacy of network requests, it cannot effectively identify abnormal behaviors in network data packets. This paper applies Adaboost algorithm in trustworthy network for anomaly intrusion detection to improve the defense capability against network attacks. This method uses a simple decision tree as the base weak learner, and uses AdaBoost algorithm to combine multiple weak learners into a strong learner by re-weighting the samples. This paper uses the real data of trustworthy network for experimental verification. The experimental results show that the average precision of network anomaly detection method based on AdaBoost algorithm is more than 0.999, indicating that it has a significant detection effect on abnormal network attacks and normal network access. Therefore, the proposed method can effectively improve the security of trustworthy networks.

In the development and study of antimicrobial peptides (AMPs), researchers have kept a watchful eye on peptides from the brevinin family because of their extensive antimicrobial activities and anticancer potency. In this study, a novel brevinin peptide was isolated from the skin secretions of the Wuyi torrent frog, Amolops wuyiensis (A. wuyiensisi), named B1AW (FLPLLAGLAANFLPQIICKIARKC). B1AW displayed anti-bacterial activity against Gram-positive bacteria Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecalis (E. faecalis). B1AW-K was designed to broaden the antimicrobial spectrum of B1AW. The introduction of a lysine residue generated an AMP with enhanced broad-spectrum antibacterial activity. It also displayed the ability to inhibit the growth of human prostatic cancer PC-3, non-small lung cancer H838, and glioblastoma cancer U251MG cell lines. In molecular dynamic (MD) simulations, B1AW-K had a faster approach and adsorption to the anionic membrane than B1AW. Therefore, B1AW-K was considered a drug prototype with a dual effect, which deserves further clinical investigation and validation.