Search

Abstract Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC.

Abstract Background Precisely estimating the probability of mental health challenges among college students is pivotal for facilitating timely intervention and preventative measures. However, to date, no specific artificial intelligence (AI) models have been reported to effectively forecast severe mental distress. This study aimed to develop and validate an advanced AI tool for predicting the likelihood of severe mental distress in college students. Methods A total of 2088 college students from five universities were enrolled in this study. Participants were randomly divided into a training group (80%) and a validation group (20%). Various machine learning models, including logistic regression (LR), extreme gradient boosting machine (eXGBM), decision tree (DT), k-nearest neighbor (KNN), random forest (RF), and support vector machine (SVM), were employed and trained in this study. Model performance was evaluated using 11 metrics, and the highest scoring model was selected. In addition, external validation was conducted on 751 participants from three universities. The AI tool was then deployed as a web-based AI application. Results Among the models developed, the eXGBM model achieved the highest area under the curve (AUC) value of 0.932 (95% CI: 0.911–0.949), closely followed by RF with an AUC of 0.927 (95% CI: 0.905–0.943). The eXGBM model demonstrated superior performance in accuracy (0.850), precision (0.824), recall (0.890), specificity (0.810), F1 score (0.856), Brier score (0.103), log loss (0.326), and discrimination slope (0.598). The eXGBM model also received the highest score of 60 based on the evaluation scoring system, while RF achieved a score of 49. The scores of LR, DT, and SVM were only 19, 32, and 36, respectively. External validation yielded an impressive AUC value of 0.918. Conclusions The AI tool demonstrates promising predictive performance for identifying college students at risk of severe mental distress. It has the potential to guide intervention strategies and support early identification and preventive measures.

Objective To assess short- and long-term changes in the upper airway, natural head position and hyoid bone position in skeletal Class Ⅲ patients after bimaxillary surgery. Methods In this retrospective study, the cone-beam computed tomography(CBCT) of skeletal Class Ⅲ patients was taken before surgery(T0), 3 months after surgery(T1) and 2 years after surgery(T2). Three-dimensional images were created to assess postoperative changes and the correlation between the upper airway, natural head position and hyoid bone was analyzed. Results Thirty skeletal Class Ⅲ patients(13 men and 17 women) who underwent bimaxillary surgery with a mean(SD)age of 21 years(a range of 17-30 years)were evaluated. A significant decrease was observed in the volume of palatopharynx, glossopharynx and total airway after T1 and T2. There was a significant correlation between changes in the position of the mandible and changes in the volume of the upper airway(P

Abstract In order to improve the service life of extrusion taps and reduce their wear, this paper adopted the coating-simulation technology to investigate the influence laws of tool coating type and coating thickness on extrusion torque, extrusion temperature and wear amount. The validity of the numerical simulation results is confirmed through internal thread extrusion experiments. The results showed that the extrusion torque and extrusion temperature of single-layer coating and composite coating showed a tendency of decreasing and then increasing with the increase of the coating thickness; the extrusion torque and extrusion temperature of the double-layer coating increased with the increase of the coating thickness; the wear amount of the three types of coatings increased with the increase of the coating thickness. The TiAlN single coating demonstrates the most pronounced impact on decreasing extrusion torque and temperature (3.82 N·m and 88.4 °C), resulting in a smooth extrusion process. The TiAlN–TiAlN double coating exhibits the lowest wear amount of 0.076 mm. The utilization of numerical simulation proves to be a dependable approach for evaluating the efficacy of tool coatings, and reasonable selection of coating type and thickness can effectively reduce the extrusion torque, extrusion temperature and wear amount.

BackgroundAdolescents often experience difficulties with sleep quality. The existing literature on predicting severe sleep disturbance is limited, primarily due to the absence of reliable tools.MethodsThis study analyzed 1966 university students. All participants were classified into a training set and a validation set at the ratio of 8:2 at random. Participants in the training set were utilized to establish models, and the logistic regression (LR) and five machine learning algorithms, including the eXtreme Gradient Boosting Machine (XGBM), Naïve Bayesian (NB), Support Vector Machine (SVM), Decision Tree (DT), CatBoosting Machine (CatBM), were utilized to develop models. Whereas, those in the validation set were used to validate the developed models.ResultsThe incidence of severe sleep disturbance was 5.28% (104/1969). Among all developed models, the XGBM model performed best in AUC (0.872 [95%CI: 0.848-0.896]), followed by the CatBM model (0.853 [95% CI: 0.821-0.878]) and DT model (0.843 [95% CI: 0.801-0.870]), whereas the AUC of the logistic regression model was only 0.822 (95% CI: 0.777-0.856). Additionally, the XGBM model had the best accuracy (0.792), precision (0.780), F1 score (0.796), Brier score (0.143), and log loss (0.444).ConclusionsThe XGBM model may be a useful tool to estimate the risk of experiencing severe sleep disturbance among adolescents.

Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ETTAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ETTAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving half-maximal degradation at a concentration of 8.38 µM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ETTAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ETTAC-2 as a promising therapeutic candidate for targeted LRG1 intervention.

To study the antifungal effect and mechanism of linalool against Fusarium oxysporum FOX-1, the causative agent of ginger Fusarium wilt, the damaging effects of different concentrations of linalool on the mycelial growth, spore germination and cell membrane of F. oxysporum FOX-1, and its control effect on ginger Fusarium wilt were systemically investigated. The results showed that linalool could significantly inhibit the mycelial growth of F. oxysporum FOX-1 in a concentration-dependent manner, and the half maximal effective concentration (EC50) and the minimum inhibitory concentration (MICs) were 1.183 and 2 g/L, respectively. The spore concentration of F. oxysporum FOX-1 treated with linalool at MIC for 6 h was (1.43 ± 0.12) × 104 spores/mL, which was significantly lower than that of the control group ((5.79 ± 0.19) × 104 spores/mL) (P < 0.05), and the spore germination rate of F. oxysporum FOX-1 treated with linalool at MIC for 12 h was (5.83 ± 2.16)%, which was significantly lower than that of the control group ((95.12 ± 3.78)%) (P < 0.05). Treatment with linalool at 1/2 MIC and MIC damaged the integrity of the cell membrane, resulting in a significant increase in relative electrical conductivity and nucleic acid leakage in the mycelial suspension and malondialdehyde (MDA) content in the mycelium, and a significant decrease in ergosterol content, finally weakening the pathogenicity of the fungus. No lesions appeared on ginger pieces after treatment with linalool at MIC for 3 days. In conclusion, linalool affects the normal physiological function of F. oxysporum FOX-1 by inhibiting its spore germination and mycelial growth and destroying its cellular structure. This study provides a new direction for the effective control of Fusarium wilt.

Introduction: Accumulating evidence has disclosed that IgA nephropathy (IgAN) could present shortly after the second dose of COVID-19 mRNA vaccine. However, the undying mechanism remains unclear and we aimed to investigate the potential molecular mechanisms. Methods: We downloaded gene expression datasets of COVID-19 mRNA vaccination (GSE201535) and IgAN (GSE104948). Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to identify co-expression modules related to the second dose of COVID-19 mRNA vaccination and IgAN. Differentially expressed genes (DEGs) were screened, and a transcription factor (TF)-miRNA regulatory network and protein-drug interaction were constructed for the shared genes. Results: WGCNA identified one module associated with the second dose of COVID-19 mRNA vaccine and four modules associated with IgAN. Gene ontology (GO) analyses revealed enrichment of cell cycle-related processes for the COVID-19 mRNA vaccine hub genes and immune effector processes for the IgAN hub genes. We identified 74 DEGs for the second dose of COVID-19 mRNA vaccine and 574 DEGs for IgAN. Intersection analysis with COVID-19 vaccine-related genes led to the identification of two shared genes, TOP2A and CEP55. The TF-miRNA network analysis showed that hsa-miR-144 and ATF1 might regulate the shared hub genes. Conclusions: This study provides insights into the common pathogenesis of COVID-19 mRNA vaccination and IgAN. The identified pivotal genes may offer new directions for further mechanistic studies of IgAN secondary to COVID-19 mRNA vaccination.

BackgroundAt present, the practice of pulmonary rehabilitation for pneumoconiosis in China is in a primary stage. The basis for formulating an individualized comprehensive pulmonary rehabilitation plan is still insufficient, which is one of the factors limiting the development of community-level rehabilitation work. ObjectiveTo formulate an exercise prescription based on maximum heart rate measured by cardiopulmonary exercise test (CPET), conduct an individualized comprehensive pulmonary rehabilitation program with the exercise prescription for patients with stable pneumoconiosis, and evaluate its role in improving exercise endurance and quality of life, thus provide a basis for the application and promotion of pulmonary rehabilitation. MethodsA total of 68 patients were recruited from the Occupational Disease Prevention Hospital of Jinneng Holding Coal Industry Group Co., Ltd. from April to August 2022 , and were divided into an intervention group and a control group by random number table method, with 34 cases in each group. All the pneumoconiosis patients participated in a baseline test. The control group was given routine drug treatment, while the intervention group received multidisciplinary comprehensive pulmonary rehabilitation treatment on the basis of routine drug treatment, including health education, breathing training, exercise training, nutrition guidance, psychological intervention, and sleep management, whose exercise intensity was determined according to the maximum heart rate provided by CPET. The rehabilitation training lasted for 24 weeks. Patients were evaluated at registration and the end of study respectively. CPET was used to measure peak oxygen uptake per kilogram (pVO2/kg), anaerobic threshold (AT), carbon dioxide equivalent of ventilation (EqCO2), maximum metabolic equivalent (METs), and maximum work (Wmax). The modified British Medical Research Council Dyspnea Questionnaire (mMRC), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), Pittsburgh Sleep Quality Index (PSQI), Chronic Obstructive Pulmonary Disease Assessment Test (CAT), and Short Form of Health Survey (SF-36) were used to evaluate the potential effect of the comprehensive pulmonary rehabilitation program. ResultsAmong the included 68 patients, 63 patients were having complete data, then 31 cases were assigned in the control group and 32 cases in the interventional group. Before the intervention, there was no significant difference in pVO2/kg, AT, EqCO2, METs, or Wmax between the two groups (P>0.05). At the end of the trail, the indicators like pVO2/kg [(19.81±2.38) mL·(min·kg)−1], AT [(14.48±2.33) mL·(min·kg)−1], METs (5.64±0.69), and Wmax [(85.25±14) W] of patients in the intervention group were all higher than those [(13.90±2.37) mL·(min·kg)−1, (11.70±1.94) mL·(min kg)−1, (3.97±0.70), and (61.77±14.72) W, respectively] in the control group (P0.05). At the end of the trail, the mMRC score (1.16±0.57), SAS score (27.93±2.12), SDS score (26.48±1.44), PSQI score (1.08±0.88), and CAT score (4.34±3.28) of patients in the intervention group were lower than those [(2.03±0.83), (35.87±6.91), (34.23±6.65), (5.37±3.03), and (13.87±7.53), respectively] in the control group (P0.05). ConclusionComprehensive pulmonary rehabilitation can increase the oxygen intake and exercise endurance of pneumoconiosis patients, ameliorate dyspnea symptoms, elevate psychological state and sleep quality, and improve the quality of life.

Background: Epithelial ovarian cancer (EOC) is among the top 5 causes of cancer-associated death in women. We explored the diagnostic value of 3.0 T magnetic resonance imaging (MRI) combined with carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) on EOC. Methods: Among 380 ovarian space-occupying patients in this retrospective analysis, 344 were included, 59 were excluded, 25 had incomplete clinical data, and 260 were finally included as the subjects. Patients were classified into the EOC (110 patients with EOC) and N-EOC (150 patients without EOC) groups. The levels of interleukin-6 (IL-6), C-reactive protein (CRP), follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), CA125, and HE4 were determined. The apparent diffusion coefficient (ADC) value and the clinical diagnostic value of MRI, CA125, HE4, and their combination were analyzed. Results: There were significant differences in tumor family history, gravidity, parity, IL-6, CRP, FSH, LH, AMH, and ADC value between EOC and N-EOC patients (all p < 0.05). EOC patients exhibited highly-expressed CA125 and HE4 (p < 0.01). CA125/HE4 expression was correlated with the clinicopathological features of EOC, while the ADC value was correlated with the EOC tumor diameter (all p < 0.05). MRI [area under the curve (AUC) = 0.77], CA125 (AUC = 0.85) and HE4 (AUC = 0.90) had certain diagnostic value for EOC (all p < 0.05). Conclusions: The prevalence of EOC in ovarian space-occupying patients with highly-expressed CA125 and HE4 is higher. MRI combined with CA125 and HE4 has high clinical diagnostic value for EOC.

A class of proteins known as antifreeze proteins (AFPs) appear in some organisms, allowing them to survive in low-temperature environments. These AFPs irreversibly adsorb to the surfaces of ice crystals and reduce the freezing temperature without significantly affecting the equilibrium melting point. Ice crystal growth is inhibited in the temperature gap between the melting point and the non-equilibrium freezing point, referred to as thermal hysteresis (TH). The irreversible adsorption of AFPs on the surfaces of ice crystals has been questioned because it is not consistent with the concentration dependence of the TH activity obtained from experimental studies. In this study, based on adsorption–inhibition theory, a random sequential adsorption model of AFPs was used to investigate the irreversible adsorption of hyperactive AFPs that have been found in the yellow mealworm beetle Tenebrio molitor (TmAFPs). The occupied fractions covered by TmAFP on ice crystal surfaces were obtained. The time and concentration dependence of the TH activity of TmAFP was analyzed. The theoretical results obtained from this model were consistent with reported experimental data. This work provides ideas and a theoretical basis for understanding the TH activity during the irreversible adsorption of AFPs.

Introduction: The carbon storage service of ecosystems in ecologically fragile areas is highly sensitive to regional land use/land cover (LULC) changes. Predicting changes in regional carbon storage under different LULC scenarios is crucial for land use management decisions and exploring carbon sink potential. This study focuses on the Luan River Basin, a typical ecologically fragile area, to analyze the impact of LULC changes on carbon storage.Methods: The PLUS-InVEST model was employed to simulate LULC patterns for the year 2030 under three scenarios: natural development, cropland protection and urban development, and ecological protection. The model projected the future carbon sink potential of the basin under these scenarios.Results: From 2000 to 2020, carbon storage showed a trend of decrease followed by an increase. By 2030, compared to 2020, carbon storage is projected to increase by 16.97% under the ecological protection scenario and decrease by 22.14% under the cropland protection and urban development scenario. The increase in carbon storage was primarily due to the conversion of cropland and grassland to forestland, while the decrease was mainly associated with the conversion of forestland to grassland and cropland, and the transformation of grassland to cropland and construction land. In the potential LULC scenarios of 2030, certain regions within the basin exhibited unstable carbon sink potential, strongly influenced by LULC changes. These areas were predominantly characterized by artificially cultivated forests, shrubs, and agricultural land. Implementing appropriate forest management measures and optimizing agricultural land management practices are essential to enhance carbon sink potential in these regions. Population density, annual average temperature, and DEM (Digital Elevation Model) were the dominant factors driving the spatial variation of carbon sink potential in the Luan River Basin.Discussion: The research results provide a theoretical basis for rational planning of land use and the enhancement of carbon sink potential in ecologically fragile regions.

Excessive cadmium (Cd) in rice, caused by Cd pollution of farmlands, poses a serious threat to human health. In this study, a pot experiment was conducted to investigate the effects of two doses of CaCO3 (Ca1: 2 g kg-1, Ca2: 10g kg-1), two types of Fe(II) (EDTA-Fe(II) and FeSO4; 0.14 g Fe kg-1), and their combined application on the uptake and accumulation of Cd in rice plants grown in Cd-contaminated acidic soil. The results revealed that FeSO4 significantly increased rice grain biomass, whereas the other treatments had no significant effects. Further, the addition of EDTA-Fe(II) or FeSO4 significantly enhanced iron plaque formation on the root surface and increased the Fe content in the rice plants and porewater. Compared to the control, CaCO3 addition weakened the formation of iron plaque and reduced the Fe concentration in the porewater and root tissue, stems and leaves, whereas the Fe concentration in brown rice and the husks remained unaffected. Combined application of CaCO3 and Fe(II) significantly promoted the formation of iron plaque and increased the Fe concentration in brown rice. However, the Cd concentration in the iron plaque was reduced by CaCO3 addition but increased by Fe(II) treatment. Notably, all treatments reduced the Cd concentration in all rice plant tissues. The application of Ca1, Ca2, EDTA-Fe(II), FeSO4, Ca1+EDTA-Fe(II), Ca1+FeSO4, Ca2+EDTA-Fe(II) and Ca2+FeSO4 significantly reduced the Cd concentration in brown rice by 69%, 63%, 51%, 60%, 46%, 39%, 38%, and 29%, respectively. These results indicate that the application of CaCO3, EDTA-Fe(II)/FeSO4, or their combination can effectively reduce Cd accumulation and translocation in rice plants.

Biodiversity loss is one of the major crises facing humanity today, and with none of the biodiversity targets represented by the Aichi Biodiversity Targets being met, there is an urgent need to promote transformative change to halt and reverse the trend of biodiversity loss. Nature-based solutions (NbS) have emerged as an important way to address the global crisis due to its inherent principles involving holistic and systemicness, diversity, stability, sustainability, trade-offs, and compatibility. The relationship between biodiversity and NbS is analyzed from a mechanistic and functional perspective, and the pathway of NbS as a proxy for biodiversity conservation is revealed by restoring of ecosystem complexity and trophic levels to put nature on the path. We here propose the dual intensions of promoting NbS for biodiversity conservation, as (1) the goal aimed at enhancing diversity, stability, and sustainability of ecosystem, and (2) the tool involves use natural processes. Based on the above understanding of the link between NbS and biodiversity, this paper further compares the conceptual connotation of NbS with the consistency of biodiversity conservation, as well as the NbS methods for biodiversity conservation including natural, agricultural and urban area. Practical cases of NbS for biodiversity conservation or synergy of NbS for biodiversity are summarized in align with differentiated typical ecosystems. The multiple benefits of NbS for biodiversity conservation, climate change and sustainable development are discussed. The vision of integrating NbS into strategic planning for biodiversity conservation is presented to provide a reference for promoting the implementation of Kunming-Montreal Global Biodiversity Framework and the mainstreaming of NbS in biodiversity conservation.

Kunming-Montreal Global Biodiversity Framework sets out key actions for biodiversity conservation worldwide in the coming period, including integrating biodiversity and its multiple values into economic and social activities. As a party to the United Nations Convention on Biological Diversity (CBD), China has made unremitting efforts to promote the biodiversity mainstreaming, integrating biodiversity conservation into top-level national decision-making and major strategic planning, and integrating it into the policies, norms and assessment mechanisms of ecological environments, natural resources and other relevant industries. Different functional departments, scientific research institutions, enterprises, social organizations and other organizations have carried out extensive and in-depth researches based on multiple aspects of biodiversity conservation and management. Benchmark the objectives of Kunming-Montreal Global Biodiversity Framework and refer the advanced experience of biodiversity mainstreaming practices in other countries, we discussed and analyzed the conceptual connotation of biodiversity mainstreaming, summarized the practice and stage results of biodiversity mainstreaming in China. Then focusing on different actors including governments, enterprises and the public, we propose the implementation path of promoting biodiversity mainstreaming in an all-round way for China in the new era, including: (1) To import a consistent action framework which is mitigation protection hierarchy with four steps, contains avoidance, mitigation, recovery, and offset; (2) To give play to the leading role of government governance, and to integrate biodiversity conservation into government governance systems and industrial development layout with the help of various planning and policy tools; (3) To support enterprises to take joint actions and internalize ecological and environmental hazards into business operations which can promote sustainable production and consumption; (4) To raise public awareness to promote broad participation in biodiversity conservation, establish a system of public participation in biodiversity conservation through various publicity and education actions, to guide the public to practice a green and low-carbon lifestyle, and to translate into real benefits of biodiversity and climate mitigation and improvement. By taking the above actions, we will strive to integrate biodiversity into the policy mechanisms of government departments at all levels and social production and life practices, so as to provide references for improving biodiversity governance decisions.

Compared to the traditional thermal power generation, new energy sources, such as wind and photovoltaic systems, are more vulnerable to the effects of non-ideal power grids due to their limited capacity. This susceptibility can jeopardize the safe operation of power equipment, degrade power output quality, and lead to non-compliance with grid-connected specifications. The LCL-type grid-connected inverter is a typical nonlinear system that weakens the controllability of the grid-connected energy. To address these challenges, this study employs feedback linearization theory to transform the inverter into a standard linear system. Subsequently, it utilizes linear system methodologies to develop robust control laws, ultimately introducing a multi-functional multiplexing control strategy for grid-connected inverters based on feedback linearization and Hamilton-Jacobi-Issacs inequality. Simulation results demonstrate that this multi-functional strategy outperforms traditional grid-connected inverter control schemes, effectively mitigating issues related to low short-circuit ratios, voltage fluctuations, imbalances, harmonics, and other non-ideal grid conditions. Furthermore, it significantly expands the system’s adaptability to varying weak grid impedances.

Saltmarsh is widely recognized as a blue carbon ecosystem with great carbon storage potential. Yet soil respiration with a major contributor of atmospheric CO2 can offset its carbon sink function. Up to date, mechanisms ruling CO2 emissions from saltmarsh soil remain unclear. In particular, the effect of precipitation on soil CO2 emissions is unclear in coastal wetlands, due the lack of outdoor data in real situations. We conducted a 7-year field manipulation experiment in a saltmarsh in the Yellow River Delta, China. Soil respiration in five treatments (−60%, −40%, +0%, +40%, and + 60% of precipitation) was measured in the field. Topsoils from the last 3 years (2019–2021) were analyzed for CO2 production potential by microcosm experiments. Furthermore, quality and quantity of soil organic carbon and microbial function were tested. Results show that only the moderate precipitation rise of +40% induced a 66.2% increase of CO2 production potential for the microcosm experiments, whereas other data showed a weak impact. Consistently, soil respiration was also found to be strongest at +40%. The CO2 production potential is positively correlated with soil organic carbon, including carbon quantity and quality. But microbial diversity did not show any positive response to precipitation sizes. r-/K-strategy seemed to be a plausible explanation for biological factors. Overall, our finding reveal that a moderate precipitation increase, not decrease or a robust increase, in a saltmarsh is likely to improve soil organic carbon quality and quantity, and bacterial oligotroph:copiotroph ratio, ultimately leading to an enhanced CO2 production.

IntroductionThe hybrid hazelnut is an important fruit tree species known for its high productivity and disease resistance. However, during the growth process of hybrid hazelnuts, issues such as branch withering and bud wrinkling have attracted significant attention. These phenomena severely impact the normal development and yield of the plants. This study aimed to investigate the relationship between the resistance to shoot emergence and physiological changes in six hazel tree varieties by comprehensively analyzing their resistance to shoot emergence.MethodSix widely cultivated hazelnut hybrid varieties were selected for physiological measurements and field surveys using one-year-old branches and buds as test materials. The resistance to shoot emergence of different hazel tree varieties was evaluated through correlation analysis, principal component analysis, and membership function evaluation.ResultsThe results showed that the length and width of hazel buds gradually increased while the thickness first increased and then decreased before and after bud burst. The carbohydrate levels of the ‘Dawei’, ‘Pingou 110’, and ‘84–237’ varieties were significantly higher than those of other varieties. The content of reducing sugars and starch in hazel buds generally increased and then decreased during the bud burst process, while α-amylase activity showed a decreasing trend followed by an increasing trend. The antioxidative enzyme activity of ‘Dawei’ was significantly higher than that of other varieties on different sampling dates. The soluble protein content, POD enzyme activity, and CAT enzyme activity of hazel buds for the six varieties gradually decreased. The moisture content of ‘Pingou 210’ shoots was significantly higher than that of other varieties during the peak emergence period. The correlation analysis results showed that the bud burst rate of hazel trees was positively correlated with the length, width, thickness, reducing sugar content, starch content, POD enzyme activity, CAT enzyme activity, and shoot moisture content, while it was negatively correlated with α-amylase activity and relative conductivity of shoots. Through a comprehensive evaluation using correlation analysis, principal component analysis, and membership function analysis, the resistance to shoot emergence of the six hazel tree varieties was ranked in the following order: ‘Dawei’, ‘Pingou 110’, ‘84–237’, ‘Pingou 210’, ‘Yuzhui’, and ‘Liaozhen 3’.DiscussionThis study fills a research gap regarding the physiological changes of hazelnuts before and after sprouting, and provides theoretical guidance for further research on the anti-withering ability of hazelnut trees.

Background: The formation of biomolecular condensates via phase separation has emerged as a fundamental principle underlying the spatiotemporal coordination of biological activities in cells. Aberrant biomolecular condensates often directly regulate key cellular process involved in the pathogenesis of human diseases, including kidney diseases. Summary: In this review, we summarize the physiological roles of phase separation and methodologies for phase separation studies. Taking autosomal dominant polycystic kidney disease as an example, we discuss recent advances toward elucidating the multiple mechanisms involved in kidney pathology arising from aberrant phase separation. We suggest that dysregulation of phase separation contributes to the pathogenesis of other important kidney diseases, including kidney injury and fibrosis. Key Messages: Phase separation provides a useful new concept to understand the mechanisms underlying kidney disease development. Targeting aberrant phase-separated condensates offers new therapeutic avenues for combating kidney diseases.

Renal tubular epithelial cells (TECs) can initiate an adaptive or maladaptive response after injuries of different severity. Here, the authors elucidate a chromatin-mediated mechanism underlying the responses of TECs to varying kidney injuries.

Abstract Diabetic retinopathy (DR) is a common microvascular complication leading to a high blindness rate among patients with diabetes. Ferroptosis is a type of cell death caused by the accumulation of iron-dependent lipid peroxides. Studies have shown that ferroptosis plays an important role in DR. The rat model of DR was constructed and treated with Ferrostatin-1 (Ferr-1). Haematoxylin and eosin (HE) were used to detect the degree of retinopathy. Oxidative stress levels were detected by ELISA. Perl’s staining was used to detect iron deposition in retinal tissues. Ferritin levels were measured by ELISA. The expression of GPX4 was detected by immunohistochemistry (IHC). GSH/GSSG kit was used to detect the content and proportion of reduced/oxidized glutathione. Western blot was used to detect the expression of ferroptosis-related proteins. TUNEL assay was used to detect cell apoptosis. The expression of GSDMD was detected by fluorescence in situ hybridization (FISH). Western blot was used to detect the expression of apoptosis and pyroptosis-related proteins. Then, high glucose (HG)-induced retinal epithelial cell line ARPE-19 was treated by Erastin (ferroptosis activator) and Ferr-1. CCK-8, ELISA, western blot, flow cytometry, and immunofluorescence (IF) staining were used to detect oxidative stress levels, ferroptosis and cell damage. The mechanism was further explored by adding ferroptosis agonist Erastin. In vitro and in vivo results showed that oxidative stress was increased in DR model, resulting in ferroptosis and tissue or cell damage. After administration of Ferr-1, the antioxidant capacity was improved, ferroptosis levels were reduced and tissue or cell damage was alleviated. In vitro results showed that Ferr-1 reversed the impacts of Erastin on oxidative stress, ferroptosis, and cell damage in HG-induced ARPE-19 cells. Ferr-1 alleviated tissue and cell damage by improving the antioxidant capacity of the Xc--GPX4 system.

The energy problem in today’s society is becoming increasingly prominent, and the smart grid has become one of the important ways to solve the energy problem. Smart grid energy storage capacity planning and scheduling optimization is an important issue in the smart grid, which can make the grid more efficient, reliable, and sustainable to meet energy demand better and protect the environment. The core of smart grid energy storage capacity planning and scheduling optimization is maximizing the use of energy storage devices to balance the difference between power supply and demand to ensure the grid operation’s stability. Traditional planning methods are usually based on experience and rules, have low precision, and cannot adapt to the dynamic changes in the long-term development of the power grid. Therefore, this paper proposes a method that combines PSO-GRU (particle swarm Optimization (PSO)-gated recurrent unit (GRU)) and Multihead-Attention to realize smart grid energy storage capacity planning. And scheduling optimization. First, PSO-GRU models and predicts power grid data by searching for the optimal GRU model parameters; second, Multihead-Attention improves the model’s performance through the self-attention mechanism. Finally, we use the method to determine the optimal energy storage capacity and dispatching scheme for the efficient operation of smart grids. Our experiments use real power grid datasets and compare them with other common methods. Experimental results show that our proposed method has higher accuracy and stability than other methods and can better adapt to the dynamic changes of the power grid. This indicates that our method has good feasibility and applicability in practical applications and is significant for realizing the efficient operation of smart grids and energy saving and emission reduction.

Summary: Levofloxacin-induced severe cutaneous adverse drug reactions (LEV-SCARs) remain unexplored. An association study of human leukocyte antigen (HLA) alleles with LEV-SCARs among 12 patients, 806 healthy subjects, and 100 levofloxacin-tolerant individuals was performed. The carrier frequencies of HLA-B∗13:01 (odds ratio [OR]: 4.50; 95% confidence interval [CI]: 1.15–17.65; p = 0.043), HLA-B∗13:02 (OR: 6.14; 95% CI: 1.73–21.76; p = 0.0072), and serotype B13 (OR: 17.73; 95% CI: 3.61–86.95; p = 4.85 × 10−5) in patients with LEV-SCARs were significantly higher than those of levofloxacin-tolerant individuals. Molecular docking analysis suggested that levofloxacin formed more stable binding models with HLA-B∗13:01 and HLA-B∗13:02 than with non-risk HLA-B∗46:01. Mass spectrometry revealed that nonapeptides bound to HLA-B∗13:02 shifted at several positions after exposure to levofloxacin. Prospective screening for serotype B13 (sensitivity: 83%, specificity: 78%) and alternative drug treatment for carriers may significantly decrease the incidence of LEV-SCARs.

Abstract Genetic kidney disease is the main cause of chronic kidney disease in children. While the pathogenic genes associated with most genetic kidney diseases have been identified, the underlying mechanisms of disease initiation remain ambiguous, and effective treatment modalities are limited. Gene therapy has emerged as a promising approach for treating genetic diseases. Several gene therapy drugs have been successfully launched to treat genetic diseases affecting the eyes and muscles. However, the development of gene therapy agents for kidney diseases lags behind that of other genetic disorders. In this review, we first comprehensively summarize the main gene therapy strategies. Next, we provide an overview of current treatment options as well as the latest research on gene therapy approaches for pediatric genetic kidney diseases with a particular emphasis on Alport syndrome and polycystic kidney disease. Finally, we discuss the challenges and potential solutions for gene therapy of pediatric genetic kidney diseases.

IntroductionDespite recent advances, there are limited treatments available for acute asthma exacerbations. Here, we investigated the therapeutic potential of GGsTop, a γ-glutamyl transferase inhibitor, on the disease with a murine model of asthma exacerbation.MethodsGGsTop was administered to mice that received lipopolysaccharide (LPS) and ovalbumin (OVA) challenges. Airway hyperresponsiveness (AHR), lung histology, mucus hypersecretion, and collagen deposition were analyzed to evaluate the hallmark features of asthma exacerbation. The level of proinflammatory cytokines and glutathione were determined with/without GGsTop. The transcription profiles were also examined.ResultsGGsTop attenuates hallmark features of the disease with a murine model of LPS and OVA driven asthma exacerbation. Airway hyperresponsiveness (AHR), mucus hypersecretion, collagen deposition, and expression of inflammatory cytokines were dramatically inhibited by GGsTop treatment. Additionally, GGsTop restored the level of glutathione. Using RNA-sequencing and pathway analysis, we demonstrated that the activation of LPS/NFκB signaling pathway in airway was downregulated by GGsTop. Interestingly, further analysis revealed that GGsTop significantly inhibited not only IFNγ responses but also the expression of glucocorticoid-associated molecules, implicating that GGsTop profoundly attenuates inflammatory pathways.ConclusionsOur study suggests that GGsTop is a viable treatment for asthma exacerbation by broadly inhibiting the activation of multiple inflammatory pathways.

IntroductionRheumatoid arthritis (RA) is a common disease mainly affecting joints of the hands and wrists. The discovery of autoantibodies in the serum of patients revealed that RA belonged to the autoimmune diseases and laid a theoretical basis for its immunosuppressive therapy. The pathogenesis of autoimmune diseases mainly involves abnormal activation and proliferation of effector memory T cells, which is closely related to the elevated expression of Kv1.3, a voltage-gated potassium (Kv) channel on the effector memory T cell membrane. Drugs blocking the Kv1.3 channel showed a strong protective effect in RA model animals, suggesting that Kv1.3 is a target for the discovery of specific RA immunosuppressive drugs.MethodsIn the present study, we synthesized LrB and studied the effects of LrB on collagen- induced arthritis (CIA) in rats. The clinical score, paw volume and joint morphology of CIA model rats were compared. The percentage of CD3+, CD4+ and CD8+ T cells in rat peripheral blood mononuclear and spleen were analyzed with flow cytometry. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-4, IL-6, IL-10 and IL-17 in the serum of CIA rats were analyzed with enzyme-linked immunosorbent assay. The IL-1b and IL-6 expression in joints and the Kv1.3 expression in peripheral blood mononuclear cells (PBMCs) were quantified by qPCR. To further study the mechanisms of immunosuppressive effects of LrB, western blot and immunofluorescence were utilized to study the expression of Kv1.3 and Nuclear Factor of Activated T Cells 1 (NFAT1) in two cell models - Jurkat T cell line and extracted PBMCs.ResultsLrB effectively reduced the clinical score and relieved joint swelling. LrB could also decrease the percentage of CD4+ T cells, while increase the percentage of CD8+ T cells in peripheral blood mononuclear and spleen of rats with CIA. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-6, IL-10 and IL-17 in the serum of CIA rats were significantly reduced by LrB. The results of qPCR showed that Kv1.3 mRNA in the PBMCs of CIA rats was significantly higher than that of the control and significantly decreased in the LrB treatment groups. In addition, we confirmed in cell models that LrB significantly decreased Kv1.3 protein on the cell membrane and inhibited the activation of Nuclear Factor of Activated T Cells 1 (NFAT1) with immune stimulus.ConclusionIn summary, this study revealed that LrB could block NFAT1 activation and reduce Kv1.3 expression in activated T cells, thus inhibiting the proliferation of lymphocytes and the release of inflammatory cytokines, thereby effectively weakening the autoimmune responses in CIA rats. The effects of immunosuppression due to LrB revealed its potential medicinal value in the treatment of RA.

The Hessian fly (HF, Mayetiola destructor) is one of the destructive pests of wheat (Triticum aestivum L.) worldwide. Resistant cultivars can effectively minimize wheat damage due to this insect pest. To identify new quantitative trait loci (QTL) for HF resistance, a population of recombinant inbred lines (RILs) was developed from a cross between the HF-resistant wheat cultivar ‘Chokwang’ and susceptible wheat ‘Ning 7840’, and phenotyped for responses to HF attack. A linkage map was constructed using 1147 single nucleotide polymorphism (SNP) markers generated from genotyping-by-sequencing (GBS). One major QTL, QHf.hwwg-6BS, for HF-resistance was identified on chromosome arm 6BS, which explained up to 84.0% of the phenotypic variation and was contributed by Chokwang. Two RILs showed recombination in the candidate interval of QHf.hwwg-6BS, which delimited QHf.hwwg-6BS to a 4.75 Mb physical interval between 6,028,601 bp and 10,779,424 bp on chromosome arm 6BS of IWGSC Chinese Spring reference genome RefSeq v2.0. Seven GBS-SNPs in the candidate interval were converted into Kompetitive allele specific polymerase chain reaction (KASP) markers. Two of them, KASP-6B112698 and KASP-6B7901215, were validated in a U.S. winter wheat panel. KASP-6B112698 was nearly diagnostic, thus can be used to screen QHf.hwwg-6BS and pyramid it with other resistance genes in breeding programs.

Wheat leaf rust, caused by the obligate biotrophic fungus Puccinia triticina Eriks. (Pt), is one of the most common wheat foliar diseases that continuously threatens global wheat production. Currently, the approaches used to mitigate pathogen infestation include the application of fungicides and the deployment of resistance genes or cultivars. However, the continuous deployment of selected resistant varieties causes host selection pressures that drive Pt evolution and promote the incessant emergence of new virulent races, resulting in the demise of wheat-resistant cultivars after several years of planting. Intriguingly, diploid wheat accessions were found to confer haustorium formation-based resistance to leaf rust, which involves prehaustorial and posthaustorial resistance mechanisms. The prehaustorial resistance in the interaction between einkorn and wheat leaf rust is not influenced by specific races of the pathogen. The induced defense mechanism, known as systemic acquired resistance, also confers durable resistance against a wide array of pathogens. This review summarizes the host range, pathogenic profile, and evolutionary basis of Pt; the molecular basis underlying wheat–Pt interactions; the cloning and characterization of wheat leaf rust resistance genes; prehaustorial and posthaustorial resistance; systemic acquired resistance; and the role of reactive oxygen species. The interplay between climatic factors, genetic features, planting dates, and disease dynamics in imparting resistance is also discussed.

Wheat leaf rust is a prevalent foliar disease in wheat worldwide. Growing resistant cultivars is an effective strategy to minimize the impact of leaf rust on yield and grain quality. Lr42 is a leaf rust resistance gene identified from Aegilops tauschii and is still effective against current predominant leaf rust races in the United States and many other countries. In this study, we developed diagnostic DNA markers for Lr42 using the sequence polymorphisms of a differentially expressed gene (TaRPM1) encoding a putative NB-ARC protein in the Lr42 candidate region identified by RNA-sequencing of two near-isogenic lines contrasting in Lr42 alleles. Markers were designed based on a deletion mutation and a single nucleotide polymorphism (SNP) in the gene. Haplotype analyses of the newly developed markers in the three diversity panels demonstrated that they are diagnostic for Lr42, and superior to previously used markers in selection accuracy. These markers have the advantages of low cost and easy assay, and they are suitable for marker-assisted selection in breeding programs with either high- or low-throughput marker screening facilities.

Wheat is one of the most important staple foods on earth. Leaf rust, stem rust and stripe rust, caused by Puccini triticina, Puccinia f. sp. graminis and Puccinia f. sp. striiformis, respectively, continue to threaten wheat production worldwide. Utilization of resistant cultivars is the most effective and chemical-free strategy to control rust diseases. Convectional and molecular biology techniques identified more than 200 resistance genes and their associated markers from common wheat and wheat wild relatives, which can be used by breeders in resistance breeding programmes. However, there is continuous emergence of new races of rust pathogens with novel degrees of virulence, thus rendering wheat resistance genes ineffective. An integration of genomic selection, genome editing, molecular breeding and marker-assisted selection, and phenotypic evaluations is required in developing high quality wheat varieties with resistance to multiple pathogens. Although host genotype resistance and application of fungicides are the most generally utilized approaches for controlling wheat rusts, effective agronomic methods are required to reduce disease management costs and increase wheat production sustainability. This review gives a critical overview of the current knowledge of rust resistance, particularly race-specific and non-race specific resistance, the role of pathogenesis-related proteins, non-coding RNAs, and transcription factors in rust resistance, and the molecular basis of interactions between wheat and rust pathogens. It will also discuss the new advances on how integrated rust management methods can assist in developing more durable resistant cultivars in these pathosystems.

The aim of this study was to develop and validate a prediction model to evaluate the risk of poor sleep quality. We performed a cross-sectional study and enrolled 1,928 college students from five universities between September and November 2021. The quality of sleep was evaluated using the Chinese version of the Pittsburgh Sleep Quality Index (PSQI). Participants were divided into a training (n = 1,555) group and a validation (n = 373) group. The training group was used to establish the model, and the validation group was used to validate the predictive effectiveness of the model. The risk classification of all participants was performed based on the optimal threshold of the model. Of all enrolled participants, 45.07% (869/1,928) had poor sleep quality (PSQI score ≧ 6 points). Multivariate analysis showed that factors such as older age, a higher grade, previous smoking, drinking, midday rest, chronic disease, anxiety, and stress were significantly associated with a higher rate of poor sleep quality, while preference for vegetables was significantly associated with better sleep quality, and all these variables were included to develop the prediction model. The area under the curve (AUC) was 0.765 [95% confidence interval (CI): 0.742–0.789] in the training group and 0.715 (95% CI: 0.664–0.766) in the validation group. Corresponding discrimination slopes were 0.207 and 0.167, respectively, and Brier scores were 0.195 and 0.221, respectively. Calibration curves showed favorable matched consistency between the predicted and actual probability of poor sleep quality in both groups. Based on the optimal threshold, the actual probability of poor sleep quality was 29.03% (317/1,092) in the low-risk group and 66.03% (552/836) in the high-risk group (P < 0.001). A nomogram was presented to calculate the probability of poor sleep quality to promote the applicationof the model. The prediction model can be a helpful tool to stratify sleep quality, especially among university students. Some intervention measures or preventive strategies to quit smoking and drinking, eat more vegetables, avoid midday rest, treat chronic disease, and alleviate anxiety and stress may be considerably beneficial in improving sleep quality.

Biotrophic plant pathogenic fungi are among the dreadful pathogens that continuously threaten the production of economically important crops. The interaction of biotrophic fungal pathogens with their hosts necessitates the development of unique infection mechanisms and involvement of various virulence-associated components. Biotrophic plant pathogenic fungi have an exceptional lifestyle that supports nutrient acquisition from cells of a living host and are fully dependent on the host for successful completion of their life cycle. The haustorium, a specialized infection structure, is the key organ for biotrophic fungal pathogens. The haustorium is not only essential in the uptake of nutrients without killing the host, but also in the secretion and delivery of effectors into the host cells to manipulate host immune system and defense responses and reprogram the metabolic flow of the host. Although there is a number of unanswered questions in this area yet, results from various studies indicate that the haustorium is the root of biotrophic fungal pathogens. This review provides an overview of current knowledge of the haustorium, its structure, composition, and functions, which includes the most recent haustorial transcriptome studies.

Docosahexaenoic acid (DHA) has been reported to suppress the tumor growth and improve prognosis and has been used to cooperate with many other chemotherapy medicines. Up to now, surveys focused on the Interaction between DHA and radiation are relatively modest. Our study sought to evaluate the radiosensitivity changes caused by DHA on esophageal cancer cells. We selected TE-1 and TE-10 esophagus cancer cells as models and performed routine cell proliferation assay and cloning assay to detect the impact of DHA combined with X-ray. We used cell cycle assay, lipid peroxidation assay, comet assay, and apoptosis assay to unearth the potential causes. We also launched a mouse transplanted tumor experiment to verify the synergetic effect of DHA and irradiation. Finally, a western blot assay was used to find a novel mechanism. As a result, DHA improved TE-1 and TE-10 radiosensitivity in vivo and in vitro. What's more, PPAR-γ expression increased due to the DHA supplement. Inhibiting PPAR-γ could attenuate benefits brought out by DHA somehow. Due to its explicit usage and convenience, DHA would serve as an adjuvant therapy before radiotherapy if the clinical trials indicated positive.

Coronavirus disease 2019 (COVID-19) vaccination regimens contribute to limiting the spread of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). However, the emergence and rapid transmission of the SARS-CoV-2 variant Omicron raise a concern about the efficacy of the current vaccination strategy. Here, we expressed monomeric and dimeric receptor-binding domains (RBDs) of the spike protein of prototype SARS-CoV-2 and Omicron variant in E. coli and investigated the reactivity of anti-sera from Chinese subjects immunized with SARS-CoV-2 vaccines to these recombinant RBDs. In 106 human blood samples collected from 91 participants from Jiangxi, China, 26 sera were identified to be positive for SARS-CoV-2 spike protein antibodies by lateral flow dipstick (LFD) assays, which were enriched in the ones collected from day 7 to 1 month post-boost (87.0%) compared to those harvested within 1 week post-boost (23.8%) (P < 0.0001). A higher positive ratio was observed in the child group (40.8%) than adults (13.6%) (P = 0.0073). ELISA results showed that the binding activity of anti-SARS-CoV-2 antibody-positive sera to Omicron RBDs dropped by 1.48- to 2.07-fold compared to its homogeneous recombinant RBDs. Thus, our data indicate that current SARS-CoV-2 vaccines provide restricted humoral protection against the Omicron variant.

Abstract Background Therapeutic tumor vaccine (TTV) that induces tumor-specific immunity has enormous potentials in tumor treatment, but high heterogeneity and poor immunogenicity of tumor seriously impair its clinical efficacy. Herein, a novel NIR responsive tumor vaccine in situ (HA-PDA@IQ/DOX HG) was prepared by integrating hyaluronic acid functionalized polydopamine nanoparticles (HA-PDA NPs) with immune adjuvants (Imiquimod, IQ) and doxorubicin (DOX) into thermal-sensitive hydrogel. Results HA-PDA@IQ NPs with high photothermal conversion efficiency (41.2%) and T 1-relaxation efficiency were using HA as stabilizer by the one-pot oxidative polymerization. Then, HA-PDA@IQ loaded DOX via π-π stacking and mixed with thermal-sensitive hydrogel to form the HA-PDA@IQ/DOX HG. The hydrogel-confined delivery mode endowed HA-PDA@IQ/DOX NPs with multiple photothermal ablation performance once injection upon NIR irradiation due to the prolonged retention in tumor site. More importantly, this mode enabled HA-PDA@IQ/DOX NPs to promote the DC maturation, memory T cells in lymphatic node as well as cytotoxic T lymphocytes in spleen. Conclusion Taken together, the HA-PDA@IQ/DOX HG could be served as a theranostic tumor vaccine for complete photothermal ablation to trigger robust antitumor immune responses.

Biotrophic plant pathogenic fungi are widely distributed and are among the most damaging pathogenic organisms of agriculturally important crops responsible for significant losses in quality and yield. However, the pathogenesis of obligate parasitic pathogenic microorganisms is still under investigation because they cannot reproduce and complete their life cycle on an artificial medium. The successful lifestyle of biotrophic fungal pathogens depends on their ability to secrete effector proteins to manipulate or evade plant defense response. By integrating genomics, transcriptomics, and effectoromics, insights into how the adaptation of biotrophic plant fungal pathogens adapt to their host populations can be gained. Efficient tools to decipher the precise molecular mechanisms of rust–plant interactions, and standardized routines in genomics and functional pipelines have been established and will pave the way for comparative studies. Deciphering fungal pathogenesis not only allows us to better understand how fungal pathogens infect host plants but also provides valuable information for plant diseases control, including new strategies to prevent, delay, or inhibit fungal development. Our review provides a comprehensive overview of the efforts that have been made to decipher the effector proteins of biotrophic fungal pathogens and demonstrates how rapidly research in the field of obligate biotrophy has progressed.

To protect the germplasm resources of Schizothorax biddulphi, we developed and used 20 pairs of polymorphic microsatellite primers to analyze the genetic diversity and structure of populations. A total of 126 samples were collected from the Qarqan River (CEC), Kizil River (KZL), and Aksu River (AKS) in Xinjiang, China. The results showed that 380 alleles were detected in 20 pairs of primers and the average number of alleles was 19.0. The effective allele numbers and Nei’s gene diversity ranged from 1.1499 to 1.1630 and 0.0962 to 0.1136, respectively. The Shannon index range suggested low levels of genetic diversity in all populations. The genetic distance between the CEC and AKS populations was the largest, and the genetic similarity was the smallest. There was a significant genetic differentiation between CEC and the other two populations. The UPGMA clustering tree was constructed based on population genetic distance, and the clustering tree constructed by individuals showed that the AKS population and KZL population were clustered together, and the CEC population was clustered separately. Also, the group structure analysis also got the same result. It can be seen that although the three populations of S. biddulphi do not have high genetic diversity, the differentiation between the populations was high and the gene flow was limited, especially the differentiation between the CEC population and the other two populations. This study not only provided genetic markers for the research of S. biddulphi but the results of this study also suggested the need for enhanced management of S. biddulphi populations.

ObjectiveTo explore the value of dual-energy computed tomography (DECT) radiomics of the regional largest short-axis lymph nodes for evaluating lymph node metastasis in patients with rectal cancer.Materials and MethodsOne hundred forty-one patients with rectal cancer (58 in LNM+ group, 83 in LNM- group) who underwent preoperative total abdominal DECT were divided into a training group and testing group (7:3 ratio). After post-processing DECT venous phase images, 120kVp-like images and iodine (water) images were obtained. The highest-risk lymph nodes were identified, and their long-axis and short-axis diameter and DECT quantitative parameters were measured manually by two experienced radiologists who were blind to the postoperative pathological results. Four DECT parameters were analyzed: arterial phase (AP) normalized iodine concentration, AP normalized effective atomic number, the venous phase (VP) normalized iodine concentration, and the venous phase normalized effective atomic number. The carcinoembryonic antigen (CEA) levels were recorded one week before surgery. Radiomics features of the largest lymph nodes were extracted, standardized, and reduced before modeling. Radomics signatures of 120kVp-like images (Rad-signature120kVp) and iodine map (Rad-signatureImap) were built based on Logistic Regression via Least Absolute Shrinkage and Selection Operator (LASSO).ResultsEight hundred thirty-three features were extracted from 120kVp-like and iodine images, respectively. In testing group, the radiomics features based on 120kVp-like images showed the best diagnostic performance (AUC=0.922) compared to other predictors [CT morphological indicators (short-axis diameter (AUC=0.779, IDI=0.262) and long-axis diameter alone (AUC=0.714, IDI=0.329)), CEA alone (AUC=0.540, IDI=0.414), and normalized DECT parameters alone (AUC=0.504-0.718, IDI=0.290-0.476)](P

Abstract Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB‐regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase‐separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P‐TEFb) and activates P‐TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2‐regulated cystogenesis‐associated genes, whose activation depends on CRTC2 condensate‐facilitated P‐TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.

Abstract Inaccuracy localization and intrinsic radioresistance of solid tumors seriously hindered the clinical implementation of radiotherapy. In this study, we fabricated hyaluronic acid-functionalized gadolinium oxide nanoparticles (HA-Gd2O3 NPs) via one-pot hydrothermal process for effective magnetic resonance (MR) imaging and radiosensitization of tumors. By virtue of HA functionalization, the as-prepared HA-Gd2O3 NPs with a diameter of 105 nm showed favorable dispersibility in water, low cytotoxicity, and excellent biocompatibility and readily entered into the cytoplasm of cancer cells by HA receptor-mediated endocytosis. Importantly, HA-Gd2O3 NPs exhibited high longitudinal relaxivity (r 1) 6.0 mM−1S−1 as MRI contrast agents and radiosensitization enhancement in a dose-dependent manner. These finds demonstrated that as-synthesized HA-Gd2O3 NPs as bifunctional theranostic agents have great potential in tumors diagnosis and radiotherapy.

Regulation of glucose metabolism by NAD-dependent ADP-ribosyltransferase is well investigated in different populations. Genetic variations NAD + ADP-ribosyltransferase has been shown to alter the activity of the enzyme and associated with susceptibility to diabetes. However, reports on neonatal diabetes are minimal. We, therefore, in the present report aimed to investigate the involvement of NAD + ADP-ribosyltransferase variants as a possible risk factor for predisposition to neonatal diabetes mellitus in Chinese patients. Neonatal subjects diagnosed with diabetes mellitus and healthy infants from a similar geographical area were enrolled at China-Japan Union Hospital of Jilin University, China. The involvement of NAD + ADP-ribosyltransferase with neonatal diabetes mellitus was investigated in DNA samples of all participants by PCR methods. One hundred Twenty neonatal diabetes mellitus cases and a matched number of healthy neonates were enrolled in the present study. GG and G SNPs of NAD + ADP-ribosyltransferase were mainly involved in developing neonatal diabetes mellitus and the individuals with GA SNPs protect responsible for protecting from neonatal diabetes mellitus. Thus, NAD + ADP-ribosyltransferase involved in neonatal diabetes mellitus and risk of developing is approx. 2 times higher compared to healthy subjects. Our finding showed that polymorphism in NAD + ADP-ribosyltransferase gene is associated with the predisposition to neonatal diabetes mellitus in Chinese. The present study also suggested that NAD + ADP-ribosyltransferase is a promising target for the treatment of neonatal diabetes mellitus and an effective care of patients. Our study results encourage conducting further investigation in the multi-centric clinical genetic study including larger samples to assesses the role of NAD + ADP-ribosyltransferase polymorphism in neonatal diabetes mellitus. Keywords: Diabetes mellitus, Type-2, Genetic variations, Polymorphism

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for Cyp2c29 and 3a11) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels. Key words: Diet-induced obesity, Overweight, High-fat diet, Drug-metabolizing enzymes, Nuclear receptors, Ontogenic expression

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype. In the presented work, we have combined several emerging technologies to build up a nanoplatform for TNBC treatment: photothermal therapy, prodrug design and tumor cell camouflage formulation. First, we synthesized a paclitaxel (PTX) based prodrug PTX-SS, and then conjugated it to the surface of gold nanorod (Au NR) @ mesoporous silica (MSN) core-shell nanoparticles (Au@MSN-NH2 NPs). Subsequently, doxorubicin (DOX) was loaded into the Au@PTXSS-MSN NPs and further coated with cell membranes isolated from MDA-MB-231 cells to form cell camouflaged Au@PTXSS-MSN/DOX@CM NPs. The Au@PTXSS-MSN/DOX@CM NPs exhibited very good DOX loading capacity and the prodrug strategy enabled the precise adjustability of PTX-SS loading to achieve the optimized ratio between PTX and DOX to maximize the synergistic effect of these two drugs, as well as enabled GSH-responsive intracellular drug release. More interestingly, the cell membrane coating not only protected the drug from premature release, but also significantly improved the targeting ability of NPs to breast cancer MDA-MB-231 cells. The NPs also showed good photothermal responsiveness with clear improvement in inhibiting MDA-MB-231 cell proliferation under laser irradiation. The in vivo studies further confirmed the effectiveness of Au@PTXSS-MSN/DOX@CM NPs on TNBC tumor inhibition in 4T1 cell grafted tumor mice model.

Background Survival heterogeneity and limited trial follow-up present challenges for estimating lifetime benefits of oncology therapies. This study used CheckMate 067 (NCT01844505) extended follow-up data to assess the predictive accuracy of standard parametric and flexible models in estimating the long-term overall survival benefit of nivolumab plus ipilimumab (an immune checkpoint inhibitor combination) in advanced melanoma. Methods Six sets of survival models (standard parametric, piecewise, cubic spline, mixture cure, parametric mixture, and landmark response models) were independently fitted to overall survival data for treatments in CheckMate 067 (nivolumab plus ipilimumab, nivolumab, and ipilimumab) using successive data cuts (28, 40, 52, and 60 mo). Standard parametric models allow survival extrapolation in the absence of a complex hazard. Piecewise and cubic spline models allow additional flexibility in fitting the hazard function. Mixture cure, parametric mixture, and landmark response models provide flexibility by explicitly incorporating survival heterogeneity. Sixty-month follow-up data, external ipilimumab data, and clinical expert opinion were used to evaluate model estimation accuracy. Lifetime survival projections were compared using a 5% discount rate. Results Standard parametric, piecewise, and cubic spline models underestimated overall survival at 60 mo for the 28-mo data cut. Compared with other models, mixture cure, parametric mixture, and landmark response models provided more accurate long-term overall survival estimates versus external data, higher mean survival benefit over 20 y for the 28-mo data cut, and more consistent 20-y mean overall survival estimates across data cuts. Conclusion This case study demonstrates that survival models explicitly incorporating survival heterogeneity showed greater accuracy for early data cuts than standard parametric models did, consistent with similar immune checkpoint inhibitor survival validation studies in advanced melanoma. Research is required to assess generalizability to other tumors and disease stages. Highlights Given that short clinical trial follow-up periods and survival heterogeneity introduce uncertainty in the health technology assessment of oncology therapies, this study evaluated the suitability of conventional parametric survival modeling approaches as compared with more flexible models in the context of immune checkpoint inhibitors that have the potential to provide lasting survival benefits. This study used extended follow-up data from the phase III CheckMate 067 trial (NCT01844505) to assess the predictive accuracy of standard parametric models in comparison with more flexible methods for estimating the long-term survival benefit of the immune checkpoint inhibitor combination of nivolumab plus ipilimumab in advanced melanoma. Mixture cure, parametric mixture, and landmark response models provided more accurate estimates of long-term overall survival versus external data than other models tested. In this case study with immune checkpoint inhibitor therapies in advanced melanoma, extrapolation models that explicitly incorporate differences in cancer survival between observed or latent subgroups showed greater accuracy with both early and later data cuts than other approaches did.

The chromosomal t(4;14) (p16;q32) translocation drives high expression of histone methyltransferase nuclear SET domain–containing 2 (NSD2) and plays vital roles in multiple myeloma (MM) evolution and progression. However, the mechanisms of NSD2-driven epigenomic alterations in chemoresistance to proteasome inhibitors (PIs) are not fully understood. Using a CRISPR/Cas9 sgRNA library in a bone marrow–bearing MM model, we found that hepatoma-derived growth factor 2 (HRP2) was a suppressor of chemoresistance to PIs and that its downregulation correlated with a poor response and worse outcomes in the clinic. We observed suppression of HRP2 in bortezomib-resistant MM cells, and knockdown of HRP2 induced a marked tolerance to PIs. Moreover, knockdown of HRP2 augmented H3K27me3 levels, consequentially intensifying transcriptome alterations promoting cell survival and restriction of ER stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylase MYC-induced nuclear antigen (MINA) to remove H3K27me3. Tazemetostat, a highly selective epigenetic inhibitor that reduces H3K27me3 levels, synergistically sensitized the anti-MM effects of bortezomib both in vitro and in vivo. Collectively, these results provide a better understanding of the origin of chemoresistance in patients with MM with the t(4;14) translocation and a rationale for managing patients with MM who have different genomic backgrounds.

The application of lignin-based adsorbents in the efficient removal of phosphate from wastewater has attracted much attention and been intensively studied in recent years. However, most currently reported lignin-based adsorbents are difficult to recover and recycle. Herein, we have developed a recyclable, nanostructured bio-adsorbent, poly(ethyleneimine) (PEI)-modified lignin (LG) integrated with Fe3O4 and Zr-La dual-metal hydroxide (LG-NH2@Fe3O4@Zr-La), by the Mannich reaction followed by the chemical coprecipitation method. Multilayer adsorption existed on the surface of LG-NH2@Fe3O4@Zr-La based on the isotherm fitting curve, and its adsorption capacity reached 57.8 mg P g−1, exhibiting a higher phosphate uptake than most reported metallic oxide-based composites. The adsorption process was dominated by inner-sphere complexation of ligand-exchange and electrostatic interactions. Moreover, LG-NH2@Fe3O4@Zr-La exhibited excellent selectivity against coexisting anions, and the adsorption was more efficient under acidic conditions. When the phosphate concentration was 2.0 mg P L−1, the removal efficiency of phosphate reached 99.5% and the residual concentration was only 10 μg P L−1, which meets the United States Environmental Protection Agency (USEPA) standard for eutrophication prevention. In addition, the LG-NH2@Fe3O4@Zr-La displayed excellent reusability, maintaining 91.8% of removal efficiency after five cycles. Importantly, owing to the magnetic properties of the loaded Fe3O4, the resulting composite could be separated within 30 s under an external magnetic field. Thus, the separable and recyclable biobased magnetic adsorbent developed in this work exhibited promising application in phosphate capture from real sewage. This research study provides a new perspective for lignin valorization in lignocellulose biorefineries and establishes an approach for developing an economical and efficient bio-adsorbent for phosphate removal from wastewater.

Inflammation is a major regulator of drug-metabolizing enzymes (DMEs), therefore contributing to the interindividual variability of drug effects. However, whether prenatal inflammation affects DMEs expression in offspring remains obscure. This study investigated the effects of prenatal lipopolysaccharide (LPS) exposure on hepatic expression of inflammatory-related genes, nuclear receptors, and DMEs in offspring mice. Prenatal LPS exposure on gestational day (GD) 10 led to higher expression of NF-κB, Pxr, and Cyp2b10, while lower expression of Car, Ahr, Cyp3a11, and Ugt1a1 in postnatal day (PD) 30 offspring. However, multiple doses of LPS exposure on GD10-14 resulted in higher levels of inflammatory-related genes, Cyp1a2, and Cyp2b10, and lower levels of Pxr and Cyp3a11 in PD30 offspring liver. For PD60 offspring, decreased hepatic expression of NF-κB and IL-6, and increased expression of Pxr and Cyp3a11 were seen in single-dose LPS groups, whereas opposite results were observed in the multiple-dose LPS groups. Notably, enhanced H3K4me3 levels in the PXR response elements of the Cyp3a11 promoter were observed in the liver of PD60 offspring mice from dams treated with multiple doses of LPS during pregnancy. Overall, this study suggests that parental LPS exposure could persistently alter the hepatic expression of DMEs, and histone modifications may contribute to the long-term effects.

Nanozymes, a new generation of enzyme mimics, have recently attracted great attention. Nanozymes could catalyze chemical reactions as biological enzymes under physiologically mild conditions with higher-efficiency catalytic activities. Moreover, nanozymes could overcome the shortcomings of natural enzymes, such as easy inactivation, high cost, and low yield. With the development of more and more smart and multi-functional nanosystems, nanozymes display great achievement in tumor biology. In this review, we outline the recent advances of nanozymes in tumor and tumor microenvironment diagnosis, therapy, and theranostics.

The purpose of this study is to investigate brain functional changes in patients with intermittent exotropia (IXT) by analyzing the amplitude of low-frequency fluctuation (ALFF) of brain activity and functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI). There were 26 IXT patients and 22 age-, sex-, education-, and handedness-matched healthy controls (HCs) enrolled who underwent rs-fMRI. The ALFF, fractional ALFF (fALFF) values in the slow 4 and slow 5 bands, and FC values were calculated and compared. The correlations between ALFF/fALFF values in discrepant brain regions and clinical features were evaluated. Compared with HCs, ALFF/fALFF values were significantly increased in the right angular gyrus (ANG), supramarginal gyrus (SMG), inferior parietal lobule (IPL), precentral gyrus (PreCG), and the bilateral inferior frontal gyri (IFG), and decreased in the right precuneus gyrus (PCUN), left middle occipital gyrus (MOG), and postcentral gyrus (PoCG) in IXT patients. The Newcastle Control Test score was negatively correlated with ALFF values in the right IFG (r = −0.738, p < 0.001). The duration of IXT was negatively correlated with ALFF values in the right ANG (r = −0.457, p = 0.049). Widespread increases in FC were observed between brain regions, mainly including the right cuneus (CUN), left superior parietal lobule (SPL), right rolandic operculum (ROL), left middle temporal gyrus (MTG), left IFG, left median cingulate gyrus (DCG), left PoCG, right PreCG, and left paracentral gyrus (PCL) in patients with IXT. No decreased FC was observed. Patients with IXT exhibited aberrant intrinsic brain activities and FC in vision- and eye movement-related brain regions, which extend current understanding of the neuropathological mechanisms underlying visual and oculomotor impairments in IXT patients.