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Summary: Milk fat is an important indicator for evaluating the quality of cow’s milk. In this study, we used bovine mammary epithelial cells (BMECs) to investigate the role and molecular mechanism of KLF4 in the regulation of milk fat synthesis. The results showed that KLF4 was more highly expressed in mammary tissues of high-fat cows compared with low-fat cows. KLF4 positively regulated the expression of genes related to milk fat synthesis in BMECs, increasing intracellular triglycerides content, and KLF4 promoted milk fat synthesis by activating the PI3K-AKT-mTOR signaling pathway. Furthermore, the results of animal experiments also confirmed that knockdown of KLF4 inhibited milk fat synthesis. In addition, yeast one-hybrid assays and dual-luciferase reporter gene assays confirmed that KLF4 directly targets and binds to the fatty acid synthase (FASN) promoter region to promote FASN transcription. These results demonstrate that KLF4 is a key transcription factor for milk fat synthesis in BMECs.

Abstract Background Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. Case Presentation The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. Conclusions The patient achieved a good quality of life during the one-month follow-up period.

Abstract Background The aim of this study was to identify the risk factors for postoperative delirium (POD) in elderly patients undergoing heart valve surgery with cardiopulmonary bypass (CPB). Methods Elderly patients undergoing elective heart valve surgery with CPB in The First Affiliated Hospital of Wenzhou Medical University between March 2022 and March 2023 were selected for this investigation. They were divided into a POD group and a non-POD group. Their baseline information was collected and recorded, and the patients were subjected to neurocognitive function assessment using the Mini-Mental State Examination and the Montreal Cognitive Assessment scales before surgery. We also recorded their intraoperative indicators such as duration of surgery, duration of CPB, duration of aortic cross-clamp, blood transfusion, and postoperative indicators such as duration of mechanical ventilation, postoperative 24-hour drainage volume, and pain score. Regional cerebral oxygen saturation was monitored intraoperatively by near-infrared spectroscopy based INVOS5100C Regional Oximeter. Patients were assessed for the occurrence of POD using Confusion Assessment Method for the Intensive Care Unit, and logistic regression analysis of risk factors for POD was performed. Results The study finally included 132 patients, with 47 patients in the POD group and 85 ones in the non-POD group. There were no significant differences in baseline information and preoperative indicators between the two groups. However, marked differences were identified in duration of surgery, duration of CPB, duration of aortic cross-clamp, duration of postoperative mechanical ventilation, postoperative length of stay in cardiac intensive care unit, postoperative length of hospital stay, intraoperative blood transfusion, postoperative pain score, and postoperative 24-hour drainage volume between the two groups (p 285 min (OR, 1.021 [95% CI, 1.008–1.035]; p = 0.002), duration of postoperative mechanical ventilation > 23.5 h (OR, 6.210 [95% CI, 1.619–23.815]; p = 0.008), and postoperative CCU stay > 3.5 d (OR, 3.927 [95% CI, 1.046–14.735]; p = 0.043) were independent risk factors of the occurrence of POD while change of rScO2 at T1>50.5 (OR, 0.832 [95% CI 0.736–0.941]; p = 0.003) was a protective factor for POD. Conclusion Duration of surgery duration of postoperative mechanical ventilation and postoperative CCU stay are risk factors for POD while change of rScO2 at T1 is a protective factor for POD in elderly patients undergoing heart valve surgery with CPB.

Abstract Background Facial infiltrating lipomatosis (FIL) is a rare condition characterized by congenital facial enlargement. Beyond its impact on physical appearance, FIL can also impair essential facial functions such as swallowing, chewing, vision, and breathing, imposing a substantial physiological and psychological burden. Currently, fewer than 80 cases of FIL have been reported, and the characteristics and management strategies for FIL remain unclear. Methods We reviewed the clinical, surgical, and radiological records of 39 FIL patients who were treated at our center. Of these, genetic testing was performed for 21 patients. Results Aberrant overgrowth involves subcutaneous fat, bones, muscles, glands, tongue, lips, and teeth. Epidermal nevi could be observed in the dermatomes innervated by the three branches of the trigeminal nerve, with the highest frequency seen in the dermatome of the mandibular branch. Four patients exhibited concurrent hemimegalencephaly (HMEG), with one case presenting HMEG on the opposite side of the FIL. Nineteen patients were confirmed to harbor the PIK3CA mutation. Thirty-three patients underwent surgical procedures, with a post resection recurrence rate of approximately 25%. Conclusions A variety of maxillofacial structures may be involved in FIL. PIK3CA mutations are important pathogenic factors. Emerging targeted therapies could present an additional treatment avenue in the future. However, surgery currently remains the predominant treatment choice for FIL. The timing and modality of surgery should be individually customized, taking into account each patient's unique circumstances. Notably, there is a significant possibility of postoperative recurrence during childhood and adolescence, necessitating early strategic planning of disease management.

Abstract. Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system. Compared with patients with other cancers, glioma patients often suffer from increased levels of psychological stress, such as anxiety and fear. Chronic stress (CS) is thought to impact glioma profoundly. However, because of the complex mechanisms underlying CS and variability in individual tolerance, the role of CS in glioma remains unclear. This review suggests a new proposal to redivide the stress system into two parts. Neuronal activity is dominant upstream. Stress-signaling molecules produced by the neuroendocrine system are dominant downstream. We discuss the underlying molecular mechanisms by which CS impacts glioma. Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

The analysis of the reluctance coil launcher (RCL) basically relies on the finite element method (FEM), but the method is time-consuming and does not meet the real-time requirements for control, which seriously hampers the expansion of engineering application areas. To address this problem, this study proposes a numerical calculation method dedicated to RCL based on the mathematical equations of electromagnetic coupling, in which the magnetic saturation problem is corrected by the inductance lookup table method, and the inductance in the coupling circuit is updated in real time according to the instantaneous current and the instantaneous position of the projectile. The accuracy of the calculation method is verified and the reasons for the errors are analyzed by establishing finite element simulation model, MATLAB/Simulink model and experimental platform for a single-stage and a three-stage RCL and comparing the obtained data. When the discharge voltage of the capacitor is 300 V, the accuracy of the projectile muzzle velocity in the single-stage and three-stage is 98.42% and 98.20% respectively, which indicates that the calculation method is correct under specific conditions. The time consumed by the method is only about 1/1000 of that of FEM, which even includes the compilation time of the software MATLAB/Simulink, illustrating the advantages of the algorithm and its application prospects.

Reluctance coil launchers usually use a pulse current formed by capacitive discharge to excite the excitation coil when launching. The pulse current peaks are high, and the projectile usually undergoes deep magnetic saturation, resulting in low launching efficiency. To address this problem, this article proposes using distributed feeder circuit to drive reluctance coil launchers, replacing the traditional single set of large-capacity capacitor discharge scheme with multiple small-capacity capacitors discharged in a time-sequential manner, so as to reduce the peak current and suppress magnetic saturation problems. The study includes two main aspects, one is to study the effect of the driving method on the launch performance and analyze the reasons; the other is to propose the calculation of the time-varying data in the launch process by the time-segmented calculation method. The efficiency of the model described in the paper is only 1.301% when using a single high-capacity capacitor for launching, while the launching efficiency is increased to 3.535% when driven by the distributed feeder circuit, indicating that the method can effectively improve the launching performance.

Purposes Owing to the varietry of electrical equipment and the complex connection between them in transformer station, there are many common problems includeng relatively limited location and picture contrast of equipment, insufficient target images and markers in practical applications, and inaccurate electrical equipment image segmentation brought by the traditional way. In this paper, CNN (Convolutional Neural Network) is combined with Transformer to form a new model for segmentation of electrical equipment, and a new SE-Transfomer (Substation Equipment Transformer) network based on codec structure is proposed. Methods To obtain the local context information, the coder extracts the spatial feature map by using CNN at first. Meanwhile, the feature map is carefully modified with multi-scale feature inputs for global feature modeling. The decoder extracts global deep features using Transformer and performs stepwise up-sampling to predict the detailed segmentation map. SE-Transfomer is extensively experimented on the dataset of Liangjiazhuang Transformer Station in Shanxi province, and its longitudinal results of Dice, Recall, Specificity, and RMSE (Root Mean Square Error) are 89.31%, 90.52%, 89.62%, and 11.32, respectively. Findings The results indicate that SE-Transfomer obtains comparable or higher results than previous state-of-the-art segmentation methods on the scanning of electrical equipment in the transformer station.

Although channel consistency and seamlessness have been regarded as two critical factors in conducting omnichannel business, their combined effect has yet to be revealed. By employing a polynomial regression, this study disentangles the combined effect of channel consistency and seamlessness on customer experience in the omnichannel context. The results indicate that enhancing channel consistency and seamlessness simultaneously can improve the omnichannel customer experience. The combined effect of a high (low) level of channel consistency and a low (high) level of channel seamlessness on the omnichannel customer experience is also positive. Data vulnerability can strengthen the combined effect of channel consistency and seamlessness on customer experience in the omnichannel context. This study not only uncovers the complex influences of different combinations of channel consistency and seamlessness but also provides new insights into conducting omnichannel retail for practitioners.

The paper comprehensively summarizes the process of China's coal mine construction technology from introduction and absorption to independent development since the founding of New China more than 70 years ago, as well as the important achievements in basic research, process innovation, technological breakthrough, equipment development and achievement transformation, involving drilling and blasting method, freezing method, grouting method, drilling method, caisson method and other drilling technology as well as coal mine rock tunneling technology. At present, the mechanization and automation level of drilling and blasting equipment mainly for drilling and blasting rock has been significantly improved, and the comprehensive drilling technology for short-segment excavation of kilometer-level deep wells has been mature, and the maximum depth of vertical shaft drilling has reached 1341.6 m.The level of geological support technology for drilling and tunneling such as freezing method and grouting method has been significantly improved, gradually replacing the curtain method, sheet pile method and dewatering method and other drilling technology. The maximum frozen depth of vertical shaft is 990 m, and the maximum frozen section of inclined shaft is 681 m. The longest inclined shaft of 5875 m is built by working face grouting, and the ground pre-grouting reinforcement depth is 1355 m.Breakthroughs have been made in the technology of mechanical rock breaking and tunneling. The maximum drilling diameter of reverse drilling rig is 6 m, and the maximum drilling depth is 562 m.The maximum drilling diameter of vertical drilling rig is 10.8 m, and the maximum drilling depth is 660 m, and the application range is gradually expanded. The drilling method of vertical tunneling machine has achieved a breakthrough of zero, which has laid a foundation for intelligent drilling of coal mine vertical shaft. The operation line of the mechanized excavation method of the rock tunnel has been formed, and the average tunneling speed of the full section tunneling machine is more than 400 m/month. In summary, the innovation and development of coal in China mine construction technology and equipment in the past 70 years has significantly improved the operation environment, construction efficiency and safety level of the coal mine tunneling, realized the unmanned and fully mechanized operation of the tunneling working face, solved the problems of the tunnel construction in each stage of coal development in China, and ensured the basic construction and mining continuous construction of coal mines. At the same time, the technical equipment developed from the coal mine construction and the successful experience have been promoted and practiced in the underground engineering fields such as hydraulic power generation, municipal rail transit, mountain traffic tunnels, water diversion tunnels, and made contributions to the construction of national key projects and the development of national economy.

Abstract Background Neuromuscular electrical stimulation (NMES) is widely used as a rehabilitation methods to restore muscle mass and function in prolonged immobilization individuals. However, its effect in mechanically ventilated patients to improve clinical outcomes remains unclear. Methods A comprehensive search was conducted using PubMed, Embase, Web of Science, PEDro, and the Cochrane Library from their inception until December 24th, 2023. The search targeted randomized controlled trials (RCTs) comparing NMES with physical therapy (PT) or usual ICU care (CG), for improving clinical outcomes in mechanically ventilated patients. We performed a network meta-analysis utilizing Stata version 14.0 and R 4.3.1. Results We included 23 RCTs comprising 1312 mechanically ventilated adults. The treatments analyzed were NMES, PT, NMES combined with PT (NMES+PT), and CG. Network meta-analyses revealed that NMES or NMES+PT significantly improved extubation success rate compared to CG, with ORs of 1.85 (95% CI: 1.11, 3.08) and 5.89 (95% CI: 1.77, 19.65), respectively. Additionally, NMES exhibited a slight decrease in extubation success rate compared with NMES+PT, with OR of 0.31 (95% CI: 0.11, 0.93). Nevertheless, neither NMES nor NMES+PT showed any significant improvement in ICU length of stay (LOS), ventilation duration, or mortality when compared with PT or CG. NMES+PT emerged as the most effective strategy for all considered clinical outcomes according to the ranking probabilities. The evidence quality ranged from “low” to “very low” in this network meta-analysis. Conclusions NMES appears to be a straightforward and safe modality for critically ill, mechanically ventilated patients. When combined with PT, it significantly improved the extubation success rate against standard ICU care and NMES alone, and showed a better ranking over PT or NMES alone for clinical outcomes. Therefore, NMES combined with PT may be a superior rehabilitation strategy for this patient group.

Abstract Objective The purpose of this study was to investigate the effectiveness of implementation of video feedback combined with peer role-playing (PRP) teaching method in medical undergraduates adopting problem-based learning (PBL) teaching mode. Methods The undergraduates of five-year clinical medicine who get enrollment of Wuhan local University from 2016 and 2018 were selected to be the research objects. The same grade level is randomly divided into several groups to carry out PBL, with 6–10 students in each group. Following the principle of voluntary participation, 34 students were enrolled in the study group and 33 students in the control group finally. The research regards group as the unit, and study report in group should be carried out to fulfill the research. In the study group, the students were asked to perform PRP report, and the report videos were used for feedback. At the same time, the control group reported by PPT, and the feedback was carried out according to the PPT. At the end of the study, the “Competency Improvement Satisfaction Questionnaire (CISQ)” was distributed to investigate students’ satisfaction with this teaching method to improve their ability, Arizona Clinical Interview Score (ACIR) was administered in Chinese by a trained teacher unrelated using PRP method to assess students’ clinical inquiry ability and communication skills, and theory test was performed to assess mastery of theoretical knowledge. Results The results show that the study group is superior to the control group in improving the interest of learning and the ability of independent learning, interpersonal communication and active problem solving. Although it is in terms of the confidence in becoming a real doctor and the ability of teamwork, language expression, clinical thinking cultivated, active knowledge acquired and understood that study group are better than the control group, the difference was not statistically significant. ACIR shows that the study group is significantly better than the control group in organization, timeline planning, and transition statements, openly questioning, smooth progress, and avoiding repetition, summarizing, understandable language, documentation and total score. There is no significant difference in eye contact and no interruption. The differences between the two groups are not statistically significant in terms of responsing to concerns, positive feedback, and additional questions. The theoretical test scores of the study group are significantly higher than those of the control group. Conclusion Video feedback combined with peer role-playing teaching method implemented in medical undergraduates adopting PBL teaching mode is effective, it could stimulate interest in learning actively, improve interpersonal communication ability, improve learning efficiency and clinical knowledge and skills, and improve the confidence of becoming a real doctor. It is worthy of further research and promotion.

AbstractAlviniconcha marisindica Okutani 2014 is a deep-sea gastropod inhabited in hydrothermal vents of the Indo-Pacific. It belongs to superfamily Abyssochrysoidea. In the present study, we report the complete mitochondrial genome of A. marisindica, which is 15,979 bp in length and contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes. The nucleotide composition is 29.19% of A, 38.22% of T, 16.88% of G, and 15.71% of C. The phylogenetic analysis indicates that A. marisindica and A. boucheti clustered in the Abyssochrysoidea clade with high bootstrap support. The mitochondrial genome of A. marisindica provides valuable molecular data for further research on the evolution of deep-sea gastropods.

Objective At present, the main viewpoint is that tibial varus is the main reason of medial knee osteoarthritis (OA), and high tibial osteotomy (HTO) is also the main alignment correction method to correct medial knee OA. In contrast, the impact of the anatomical alignment of the femur on medial knee OA is often overlooked. We evaluated the increased risk for medial knee OA because a varus alignment could be attributed to the anatomical reasons that include hip anatomy, femoral shaft bowing (FSB) and femoral condylar dysplasia. Methods The present research adopted a cross‐sectional study method. We selected 62 patients with HTO in the Third Hospital of Hebei Medical University from June 2021 to March 2022 as the HTO group and 55 healthy volunteers as the control group. Femoral neck‐shaft angle (NSA), lateral FSB, mechanical lateral distal femoral angle (mLDFA) and hip‐knee‐ankle (HKA) was radiographically examined within the two groups. The femoral neck length and offset were also measured, and the ratio is represented by the ratio of the femoral neck length to off‐set (N/O). The 2‐tailed Student t‐test was used to compare the differences between groups when the data were in accordance with a normal distribution. Otherwise, the Mann–Whitney U tests was used to compare the differences between groups. Result Compared to the control group, the HTO group had a higher offset (p

Abstract Background The excellent efficacy is mitigated by the limited safety profile of microfocused ultrasound procedures. Objective We sought to assess the safety and tightening efficacy of a novel microfocused ultrasound. Methods The randomized middle and lower face and submental region of the participants were treated with the novel device using the following transducers: M4.5, D4.5, M3.0, and D3.0. Improvement in paired comparison of pretreatment and posttreatment photographs, three-dimensional (3D) volumetric assessments, skin thickness measured by B-ultrasonography, and skin photoaging parameters were evaluated. Adverse events and patient satisfaction were also recorded. Results A total of 20 participants (20 female) were enrolled. Fourteen of 20 participants (70%) were judged to show clinically significant facial tightening during 3-month follow-up (P

Abstract Effective antiviral treatments for coronavirus disease 2019 (COVID‐19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK‐4482, EIDD‐2801) is an orally administered, ribonucleoside prodrug of β‐D‐N4‐hydroxycytidine (NHC) with submicromolar potency against SARS‐CoV‐2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non‐hospitalized participants with COVID‐19, a phase II trial in hospitalized participants with COVID‐19, and a phase II/III trial in non‐hospitalized participants with COVID‐19. Molnupiravir pharmacokinetics (PK) was best described by a two‐compartment model with a transit‐compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less‐than‐proportionally (power 0.412) and was estimated as 70.6 L/h in 80‐kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild‐to‐moderate renal or mild hepatic impairment.

Abstract Background Corynebacterium pyruviciproducens is a recently described species of Corynebacterium. There are few reports on the microbiological characteristics of the new species, and there is a lack of reports on the genomic analysis of the species. Results This study involved a clinical isolate from the pus of a hospital patient with sebaceous gland abscesses. The clinically isolated strain was identified as C. pyruviciproducens strain WYJY-01. In this study, referring to Koch’s postulates, we observed the pathological changes of animal models infected by intraperitoneal injection and subcutaneous injection of pure culture of the strain WYJY-01. Furthermore, the strain WYJY-01 was isolated and cultured again from animal models' subcutaneous abscess drainage fluid. Subsequently, the genomics of the strain WYJY-01 was analyzed. By comparing various gene databases, this study predicted the core secondary metabolite gene cluster of the strain WYJY-01, virulence factor genes carried by prophage, pathogenicity islands, and resistance islands. In addition, the genomes of C. pyruviciproducens strain WYJY-01, ATCC BAA-1742 T, and UMB0763 were analyzed by comparative genomics, and the differential genes of strain WYJY-01 were compared, and their functions were analyzed. Conclusion The findings showed that the strain WYJY-01 had pathogenicity, supplementing the phenotype characteristics of C. pyruviciproducens. Meanwhile, this research revealed the possible molecular mechanism of the pathogenicity of the strain WYJY-01 at the gene level through whole genome sequence analysis, providing a molecular basis for further research.

Abstract Wind has been admitted as one of the most promising renewable energy resources in multinational regionalization policies. However, the energy conversion and utilization are challenging due to the technique reliability and cost issues. Hydraulic wind turbine (HWT) may solve the above problems. HWT is taken as a research object, and the maximum power point tracking (MPPT) control strategy is proposed collaborating with active disturbance rejection control (ADRC) and linear quadratic regulator (LQR) control methods, to solve multiplicative nonlinearity problems in the plant models and the influence of external disturbance on control performance in the MPPT control process. A nonlinear simulation model is built to explain the main findings from the experiments and obtain a better understanding of the effect of time‐varying system parameters and random fluctuation in wind speed. The collaborative control algorithm is experimentally verified on a 24‐kW HWT semi‐physical test platform that results in a promising energy conversion rate, plus the hydraulic parameters can satisfy the demand, accordingly. Ultimately, the potential challenges of implementing this technique in a smart wind energy conversion system are discussed to give a further design guidance, either theoretically or practically.

Background: Laryngeal squamous cell carcinoma (LSCC) is a common cancer of the head and neck in humans. The 5-years survival rate of patients with LSCC have declined in the past four decades. microRNAs (miRNAs) has been reported to be capable of predicting the prognosis outcomes of patients with different cancers. However, there are no reports on the usage of multi-miRNAs model as signature for the diagnosis or prognosis of LSCC. Methods: To establish the miRNAs expression-associated model for diagnosis, prognosis prediction and aided therapy of patients with LSCC, the present study enrolled 107 patients with LSCC in clinic and obtained 117 LSCC samples data from TCGA database for evaluation, respectively. Next generation sequencing (NGS), raw data processing, the least absolute shrinkage and selection operator algorithm, Cox regression analysis, construction of nomogram and cell function assays (including proliferation, migration and invasion assays) were sequentially performed. Results: There were massively dysregulated miRNAs in the LSCC compared to normal tissues. A six-miRNAs signature consists of miR-137–3p, miR-3934–5p, miR-1276, miR-129–5p, miR-7-5p and miR-105–5p was built for prognosis prediction of LSCC patients. The six-miRNAs signature is strongly associated with the poor overall survival (OS, p = 2.5e-05, HR: 4.30 [2.20–8.50]), progression free interval (PFI, p = 0.025, HR: 1.94 [1.08–3.46]) and disease specific survival (DSS, p = 1.1e-05, HR: 5.00 [2.50–10.00]). A nomogram for prediction of 2-, 3- and 5-years OS was also developed based on the six-miRNAs signature and clinical features. Furthermore, blocking the function of each of the six miRNAs inhibited proliferation, invasion and migration of LSCC cells. Conclusions: The performance of six-miRNAs signature described in the current study demonstrated remarkable potential for progression assessment of LSCC. Moreover, the six-miRNAs signature may serve as predictive tool for prognosis and therapeutic targets of LSCC in clinic.

Little studies evaluated the effectiveness of booster vaccination of inactivated COVID-19 vaccines against being infected (susceptibility), infecting others (infectiousness), and spreading the disease from one to another (transmission). Therefore, we conducted a retrospective cohort study to evaluate the effectiveness of booster vaccination of inactivated COVID-19 vaccines against susceptibility, infectiousness, and transmission in Shenzhen during an Omicron BA.2 outbreak period from 1 February to 21 April 2022. The eligible individuals were classified as four sub-cohorts according to the inactivated COVID-19 vaccination status of both the close contacts and their index cases: group 2-2, fully vaccinated close contacts seeded by fully vaccinated index cases (reference group); group 2-3, booster-vaccinated close contacts seeded by fully vaccinated index cases; group 3-2, fully vaccinated close contacts seeded by booster-vaccinated index cases; and group 3-3, booster-vaccinated close contacts seeded by booster-vaccinated index cases. Univariate and multivariate logistic regression analyses were applied to estimate the effectiveness of booster vaccination. The sample sizes of groups 2-2, 2-3, 3-2, and 3-3 were 846, 1,115, 1,210, and 2,417, respectively. We found that booster vaccination had an effectiveness against infectiousness of 44.9% (95% CI: 19.7%, 62.2%) for the adults ≥ 18 years, 62.2% (95% CI: 32.0%, 78.9%) for the female close contacts, and 60.8% (95% CI: 38.5%, 75.1%) for the non-household close contacts. Moreover, booster vaccination had an effectiveness against transmission of 29.0% (95% CI: 3.2%, 47.9%) for the adults ≥ 18 years, 38.9% (95% CI: 3.3%, 61.3%) for the female close contacts, and 45.8% (95% CI: 22.1%, 62.3%) for the non-household close contacts. However, booster vaccination against susceptibility did not provide any protective effect. In summary, this study confirm that booster vaccination of the inactivated COVID-19 vaccines provides low level of protection and moderate level of protection against Omicron BA.2 transmission and infectiousness, respectively. However, booster vaccination does not provide any protection against Omicron BA.2 susceptibility.

Background: The immune-inflammatory pathway plays a critical role in myocardial infarction development. However, few studies have systematically explored immune-related genes in relation to myocardial infarction prognosis using bioinformatic analysis. Our study aims to identify differentially expressed immune-related genes(DEIRGs) in ST-segment elevation myocardial infarction (STEMI) patients and investigate their association with clinical outcomes. Materials and methods: We conducted a systematic review of Gene Expression Omnibus datasets, selecting GSE49925, GSE60993, and GSE61144 for analysis. DEIRGs were identified using GEO2R and overlapped across the chosen datasets. Functional enrichment analysis elucidated the DEIRGs' biological functions and pathways. We established an optimal prognostic prediction model using LASSO penalized Cox proportional hazards regression. The signature's clinical utility was evaluated through survival analysis, ROC curve assessment, and decision curve analysis. Additionally, we constructed a prognostic nomogram for survival rate prediction. External validation was performed using our own plasma samples. Results: The resulting prognostic signature integrated two dysregulated DEIRGs (S100A12 and IL2RB) and two clinical variables (serum creatinine level and Gensini score). This signature effectively stratified patients into low- and high-risk groups. Survival analysis, ROC curve analysis, and decision curve analysis demonstrated its robust predictive performance and clinical utility within the first two years post-disease onset. External validation confirmed significant outcome differences between risk groups. Conclusions: Our study establishes a prognostic signature that combines DEIRGs and clinical variables for STEMI patients. The signature exhibits promising predictive capabilities for patient stratification and survival risk assessment.

The antibiotics are generally regarded as the first choice approach to treat dairy mastitis, targeting the public health problems associated with the food safety and the emergence of antibioticresistant bacteria. The objective of the study was to evaluate the antibacterial efficacy of ursolic acid (UA) when used to treat Staphylococcus aureus and other isolates associated with bovine mastitis and to clarify the mechanistic basis for these effects. The bacteriostatic properties of UA extracted from Rosmarinus officinalis L. at four different purity levels were assessed by calculating minimum inhibitory concentration (MIC) values, while the synergistic effects of combining 98% UA with antibiotics were evaluated by measuring the fractional inhibitory concentration index (FICI). Changes in biofilm formation and the growth curves of the clinical isolates were assessed to clarify the bacteriostatic effect of UA. Furthermore, the cell wall integrity, protein synthesis, and reactive oxygen species (ROS) production were assessed to determine the antibacterial mechanism of UA treatment. Ultimately, UA was revealed to exhibit robust activity against Gram-positive bacteria including S. aureus (ATCC 25923), Streptococcus dysgalactiae (ATCC27957), Streptococcus agalactiae (ATCC13813), Enterococcus faecalis (ATCC29212), and Streptococcus mutans (ATCC25175). However, it did not affect Escherichia coli (ATCC 25922). The MIC values of UA preparations that were 98, 50, 30, and 10% pure against S. aureus were 39, 312, 625, and 625 μg/mL, respectively, whereas the corresponding MIC for E. coli was >5,000 μg/mL. The minimum bactericidal concentrations of 98% UA when used to treat three clinical S. aureus isolates (S4, S5, and S6) were 78, 78, and 156 μg/mL, respectively. Levels of biofilm formation for clinical S. aureus isolates decreased with increasing 98% UA concentrations. Above the MIC dose, UA treatment resulted in the dissolution of bacterial cell walls and membranes, with cells becoming irregularly shaped and exhibiting markedly impaired intracellular protein synthesis. S. aureus treated with 98% UA was able to rapidly promote intracellular ROS biogenesis. Together, these data highlight the promising utility of UA as a compound that can be used together with other antibiotics for the treatment of infections caused by S. aureus.

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors.Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms.Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms.Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.

Background Glioblastoma (GBM) is a fatal primary brain malignancy in adults. Previous studies have shown that cytomegalovirus (CMV) is a risk factor for tumorigenesis and aggressiveness for glioblastoma. However, little is known about how CMV infection affects immune cells in the tumor microenvironment of GBM. Furthermore, there has been almost no engineered T-cell receptor (TCR)-T targeting CMV for GBM research to date.Methods We evaluated the CMV infection status of patients with GBM’s tumor tissue by immune electron microscopy, immunofluorescence, and droplet digital PCR. We performed single-cell RNA sequencing for CMV-infected GBM to investigate the effects of CMV on the GBM immune microenvironment. CellChat was applied to analyze the interaction between cells in the GBM tumor microenvironment. Additionally, we conducted single-cell TCR/B cell receptor (BCR) sequencing and Grouping of Lymphocyte Interactions with Paratope Hotspots 2 algorithms to acquire specific CMV-TCR sequences. Genetic engineering was used to introduce CMV-TCR into primary T cells derived from patients with CMV-infected GBM. Flow cytometry was used to measure the proportion and cytotoxicity status of T cells in vitro.Results We identified two novel immune cell subpopulations in CMV-infected GBM, which were bipositive CD68+SOX2+ tumor-associated macrophages and FXYD6+ T cells. We highlighted that the interaction between bipositive TAMs or cancer cells and T cells was predominantly focused on FXYD6+ T cells rather than regulatory T cells (Tregs), whereas, FXYD6+ T cells were further identified as a group of novel immunosuppressive T cells. CMV-TCR-T cells showed significant therapeutic effects on the human-derived orthotopic GBM mice model.Conclusions These findings provided an insight into the underlying mechanism of CMV infection promoting the GBM immunosuppression, and provided a novel potential immunotherapy strategy for patients with GBM.

Chronic kidney disease (CKD) represents a significant global health concern, with renal fibrosis emerging as a prevalent and ultimate manifestation of this condition. The absence of targeted therapies presents an ongoing and substantial challenge. Accumulating evidence suggests that the integrity and functionality of mitochondria within renal tubular epithelial cells (RTECs) often become compromised during CKD development, playing a pivotal role in the progression of renal fibrosis. Mitophagy, a specific form of autophagy, assumes responsibility for eliminating damaged mitochondria to uphold mitochondrial equilibrium. Dysregulated mitophagy not only correlates with disrupted mitochondrial dynamics but also contributes to the advancement of renal fibrosis in CKD. While numerous studies have examined mitochondrial metabolism, ROS (reactive oxygen species) production, inflammation, and apoptosis in kidney diseases, the precise pathogenic mechanisms underlying mitophagy in CKD remain elusive. The exact mechanisms through which modulating mitophagy mitigates renal fibrosis, as well as its influence on CKD progression and prognosis, have not undergone systematic investigation. The role of mitophagy in AKI has been relatively clear, but the role of mitophagy in CKD is still rare. This article presents a comprehensive review of the current state of research on regulating mitophagy as a potential treatment for CKD. The objective is to provide fresh perspectives, viable strategies, and practical insights into CKD therapy, thereby contributing to the enhancement of human living conditions and patient well-being.

Abstract The substantial increase in discarded face masks since the onset of the COVID‐19 pandemic has resulted in extensive environmental pollution from plastic waste. This study presents a novel upcycling method to repurpose disposable face masks into a carbon‐based nanomaterial for use in supercapacitors. The upcycled sample, CSDFM@800, demonstrates very good supercapacitor properties, boasting a high specific capacitance of 234 F g−1 at a current density of 0.5 A g−1. Additionally, the symmetric coin cell supercapacitor constructed from this material exhibits excellent performance, achieving a high energy density of 8.54 Wh kg−1 at a low current density of 0.5 A g−1, and maintaining superior capacitance retention of 96.8 % after 15,000 charge/discharge cycles at a current density of 10 A g−1. Materials characterisation results and electrochemical analysis reveal that this upcycling process not only preserves the carbon nanofiber structure but also introduces highly reactive sulfur as a heteroatom doping element.

Abstract Hepatocellular carcinoma (HCC) is a form of malignancy with limited curative options available. To improve therapeutic outcomes, it is imperative to develop novel, potent therapeutic modalities. Ketoconazole (KET) has shown excellent therapeutic efficacy against HCC by eliciting apoptosis. However, its limited water solubility hampers its application in clinical treatment. Herein, a mitochondria‐targeted chemo‐photodynamic nanoplatform, CS@KET/P780 NPs, is designed using a nanoprecipitation strategy by integrating a newly synthesized mitochondria‐targeted photosensitizer (P780) and chemotherapeutic agent KET coated with chondroitin sulfate (CS) to amplify HCC therapy. In this nanoplatform, CS confers tumor‐targeted and subsequently pH‐responsive drug delivery behavior by binding to glycoprotein CD44, leading to the release of P780 and KET. Mechanistically, following laser irradiation, P780 targets and destroys mitochondrial integrity, thus inducing apoptosis through the enhancement of reactive oxygen species (ROS) buildup. Meanwhile, KET‐induced apoptosis synergistically enhances the anticancer effect of P780. In addition, tumor cells undergoing apoptosis can trigger immunogenic cell death (ICD) and a longer‐term antitumor response by releasing tumor‐associated antigens (TAAs) and damage‐associated molecular patterns (DAMPs), which together contribute to improved therapeutic outcomes in HCC. Taken together, CS@KET/P780 NPs improve the bioavailability of KET and exhibit excellent therapeutic efficacy against HCC by exerting chemophototherapy and antitumor immunity.

This article draws inspiration from the derivation of the failure model of ordinary components under impulse loads and obtains a calculation method for the forced outage rate of power equipment under impulse loads. Based on the revised forced outage rate, the reliability of the power system under impulse loads is evaluated. By comparing and analyzing the reliability of the power grid under two scenarios: impulse loads and conventional loads, the impact of impulse loads on the operational risk of the power grid is obtained.

Abstract Like other monoclonal antibodies, immune checkpoint inhibitors may be immunogenic in some patients, potentially affecting pharmacokinetics (PKs) and clinical outcomes. In post hoc analyses, we characterized antidrug antibody (ADA) development with avelumab monotherapy in patients with metastatic Merkel cell carcinoma (mMCC) from the JAVELIN Merkel 200 trial (first‐line [1L; N = 116] and second‐line or later [≥2L; N = 88] cohorts) or with advanced urothelial carcinoma (aUC) from the JAVELIN Bladder 100 (1L maintenance [N = 350]) and JAVELIN Solid Tumor (≥2L [N = 249]) trials. Treatment‐emergent ADAs developed in a numerically higher proportion of patients with aUC (1L maintenance, 19.1%; ≥2L, 18.1%) versus mMCC (1L, 8.2%; ≥2L, 8.9%); incidences within tumor types were similar by line of therapy. In PK analyses, numerically lower avelumab trough concentration and higher baseline clearance were observed in treatment‐emergent ADA+ versus ADA− subgroups; however, differences were not clinically relevant. Numerical differences in overall survival, progression‐free survival, or objective response rate by ADA status were observed; however, no clinically meaningful trends were identified. Proportions of patients with treatment‐emergent adverse events (TEAEs; any grade or grade 3/4), serious TEAEs, TEAEs leading to treatment discontinuation, or infusion‐related reactions were similar, with overlapping 80% confidence intervals between ADA subgroups. Efficacy and safety observations were similar in subgroups defined by early development of ADA+ status during treatment. In conclusion, no meaningful differences in PKs, efficacy, and safety were observed between subgroups of avelumab‐treated patients with different ADA status. Overall, these data suggest that ADAs are not relevant for treatment decisions with avelumab.

As a common industrial solid waste, fly ash requires proper processing and utilization to alleviate environmental pressure. In contrast to earlier low-value treatment methods for fly ash, such as its use in construction materials, it is more practical to explore the high-value utilization of fly ash, considering its elemental ingredient and morphological characteristics. Herein, this work comprehensively reviews the methods and research progress of extracting and preparing silica, alumina, and zeolite respectively derived from silicon and aluminum elements in fly ash. Specifically, the mechanisms and processes of various methods are elucidated in detail, and the virtues and drawbacks of the production technologies are compared to identify a more economical and environmentally friendly method. Importantly, this work first reviews the utilization of fly ash in energy storage electrode materials. Different synthesis and treatment strategies are thoroughly examined, especially in fully utilizing fly ash as a primary resource, converting it into energy storage materials. Finally, this paper summarizes the opportunities and challenges associated with the high-value utilization of fly ash.

BackgroundNeglect is a common form of abuse, and long-term care facilities record higher incidences of this abuse. Given that older adult care workers are the main workforce in these facilities, their neglectful behavior requires public health attention. Internal individual characteristics can lead to older adult abuse, and managing workers who abuse older adults may require various methods. This study aimed to identify the profiles of neglect among older adult care workers in long-term care facilities and explore the influencing factors of neglect.MethodsIn this cross-sectional study, a convenience sample of older adult care workers from 15 long-term care facilities in Shandong Province (N = 421) completed a questionnaire on the characteristics associated with neglect. Latent profile analysis was used to identify distinct neglect profiles and promote the understanding of individual characteristics associated with varying levels of neglect. One-way analysis of variance and multivariate logistic regression analyses were used to examine the population characteristic differences.ResultsOlder adult care workers exhibited three neglect profiles, namely, the “low-risk group,” “medium-risk group,” and “high-risk group.” Males, participants with no employment qualification certificate, and those who did not attend regular training represented the majority of those in the “high-risk group.” Participants with a monthly income of more than ¥ 4,000 and nursing 1–2 older adults simultaneously represented the majority of those in the “low-risk group.”ConclusionLong-term care facility administrators should tailor interventions to individual care worker profiles to reduce neglect behaviors and improve care levels.

Projectors are common display devices in the educational setting. However, dim projector lightbulbs or well-lit classrooms may cause blurriness in the projected image. To determine the optimal projection light under different ambient light conditions, the conjoint effects of projection illuminance and ambient illuminance on the legibility of projection images indoors were investigated. Participants (N = 96) were randomly assigned to one of six indoor ambient light conditions (0, 40, 80, 120, 160, and 200 lx) and performed a visual search task under several projection illuminance conditions (200, 250, 300, 350, and 400 lx). The accuracy and correct response time on the task were collected to evaluate the participants’ visual performance to represent legibility. The optimal projection illuminance (high visual accuracy and fast reaction) was 400 lx (944 ANSI lumen) under all ambient light conditions. To avoid low legibility (accuracy0.7), the projection illuminance should be increased as the indoor ambient light increases.

Glycyrrhiza (Fabaceae) species are rich in metabolites and widely used in medicine. Research on the chloroplast genome of Glycyrrhiza is important for understanding its phylogenetics, biogeography, genetic diversity, species identification, and medicinal properties. In this study, comparative genomics and phylogenomics of Glycyrrhiza were analyzed based on the chloroplast genome. The chloroplast genomes of six Glycyrrhiza species were obtained using various assembly and annotation tools. The final assembled chloroplast genome sizes for the six Glycyrrhiza species ranged from 126,380 bp to 129,115 bp, with a total of 109–110 genes annotated. Comparative genomics results showed that the chloroplast genomes of Glycyrrhiza showed typically lacking inverted repeat regions, and the genome length, structure, GC content, codon usage, and gene distribution were highly similar. Bioinformatics analysis revealed the presence of 69–96 simple sequence repeats and 61–138 long repeats in the chloroplast genomes. Combining the results of mVISTA and nucleotide diversity, four highly variable regions were screened for species identification and relationship studies. Selection pressure analysis indicated overall purifying selection in the chloroplast genomes of Glycyrrhiza, with a few positively selected genes potentially linked to environmental adaptation. Phylogenetic analyses involving all tribes of Fabaceae with published chloroplast genomes elucidated the evolutionary relationships, and divergence time estimation estimated the chronological order of species differentiations within the Fabaceae family. The results of phylogenetic analysis indicated that species from the six subfamilies formed distinct clusters, consistent with the classification scheme of the six subfamilies. In addition, the inverted repeat-lacking clade in the subfamily Papilionoideae clustered together, and it was the last to differentiate. Co-linear analysis confirmed the conserved nature of Glycyrrhiza chloroplast genomes, and instances of gene rearrangements and inversions were observed in the subfamily Papilionoideae.

Ultraviolet (UV)-B radiation is considered one of the major detrimental rays coming from the Sun. UV-B radiation has a harmful impact on plant growth and development. The effect of UV-B radiation was studied on 64 rice (Oryza sativa L.) genotypes during the vegetative season. An equal number of genotypes from the japonica (50%) and indica (50%) subspecies were phenotyped using the Soil-Plant-Atmosphere-Research (SPAR) units. The 10 kJ UV-B was imposed 12 days after planting (DAP) and continued for three weeks (21 d). Based on the combined ultraviolet-B radiation response index (CUVBRI) for each genotype, the 64 rice genotypes were classified into sensitive, moderately sensitive, moderately tolerant, and tolerant. Various shoot traits, such as plant height, tiller, and leaf numbers, were measured. We also studied critical root phenological traits like root volume, diameter, tips, and forks. Out of all the studied shoot traits, leaf area showed maximum reduction for both indica (54%) and japonica (48%). Among the root traits, root length decreased by negligible (1%) for indica as compared to japonica (5%), while root crossing and forks showed a maximum decline for japonica (37 and 42%), respectively. This study is timely, meaningful, and required because it will help breeders select a tolerant or sensitive rice line for better yield and production under abiotic stresses.

In order to develop a multi-principal element alloy with outstanding soft magnetic properties and high thermal stability, a Fe35Co35Mn30−xAlx (x = 9, 12, 15, 18, 21, 24) alloy system was designed. The findings demonstrated that the optimal Al/Mn content ratio contributes to the formation of a BCC and B2 dual-phase structure, which leads to a significant increase in the saturation magnetic flux density (Bs) and a considerable decrease in the coercivity of the alloy. The as-cast Fe35Co35Mn15Al15 alloy with a co-lattice structure exhibits exceptional soft magnetic properties, with a resistivity of 324 μΩ·cm, a Bs of 1.46 T and a Hc of 167.2 A/m. Corresponding soft magnetic powder cores (SMPCs) were fabricated and the impact of heat treatment temperature on the properties of the SMPCs was examined. The SMPCs after annealing at 660 °C exhibits high stable permeability (μe) of 48 up to 10 MHz, a low core loss (Pcv) of 1208 mW/cm3 (at 1 MHz, 20 mT), and excellent direct current bias performance. In addition, these SMPCs possess excellent high temperature magnetic stability, and the variation of both μe and Pcv at a high frequency (1 MHz) is less than 2 % over a wide temperature range of 25–150 °C.

Abstract Hyperglycemia-induced aberrant glucose metabolism is a causative factor of neurodegeneration and cognitive impairment in diabetes mellitus (DM) patients. The pyruvate dehydrogenase kinase (PDK)–lactic acid axis is regarded as a critical link between metabolic reprogramming and the pathogenic process of neurological disorders. However, its role in diabetic neuropathy remains unclear. Here, we found that PDK1 and phosphorylation of pyruvate dehydrogenase (PDH) were obviously increased in high glucose (HG)-stimulated primary neurons and Neuro-2a cell line. Acetyl-coA, a central metabolic intermediate, might enhance PDK1 expression via histone H3K9 acetylation modification in HG condition. The epigenetic regulation of PDK1 expression provided an available negative feedback pattern in response to HG environment-triggered mitochondrial metabolic overload. However, neuronal PDK1 was decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Our data showed that the expression of PDK1 also depended on the hypoxia-inducible factor-1 (HIF-1) transcriptional activation under the HG condition. However, HIF-1 was significantly reduced in the hippocampus of diabetic mice, which might explain the opposite expression of PDK1 in vivo. Importantly, overexpression of PDK1 reduced HG-induced reactive oxygen species (ROS) generation and neuronal apoptosis. Enhancing PDK1 expression in the hippocampus ameliorated STZ-induced cognitive impairment and neuronal degeneration in mice. Together, our study demonstrated that both acetyl-coA-induced histone acetylation and HIF-1 are necessary to direct PDK1 expression, and enhancing PDK1 may have a protective effect on cognitive recovery in diabetic mice. Schematic representation of the protective effect of PDK1 on hyperglycemia-induced neuronal injury and memory loss. High glucose enhanced the expression of PDK1 in an acetyl-coA-dependent histone acetylation modification to avoid mitochondrial metabolic overload and ROS release. However, the decrease of HIF-1 may impair the upregulation of PDK1 under hyperglycemia condition. Overexpression of PDK1 prevented hyperglycemia-induced hippocampal neuronal injury and memory loss in diabetic mice.

Abstract Background Proper lower limb alignment and soft tissue balance are significant indicators to measure the success of total knee arthroplasty (TKA). Previous studies have confirmed that soft tissue relaxation around the knee after TKA will change over time; however, the relationship between lower limb alignment and soft tissue balance after TKA remains unclear. We studied (1) whether the change of soft tissue balance around the knee with time after posterior-stabilized (PS) TKA would affect the alignment of the lower limbs; (2) Whether the accuracy of lower limb alignment during PS TKA affects postoperative soft tissue remodeling. Methods In this study, 100 patients were recruited after PS TKA. Among them, 50 patients with a hip knee ankle (HKA) angle of ≤ ± 3° were set as the neutral group, and 50 patients with an HKA angle of > ± 3° were set as the deviation group. The imaging results measured the HKA angle before the operation as well as the HKA, varus, and valgus angles at 1, 3, 6, 12, and 24 months after TKA. Clinical assessment included range of motion (ROM), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Society Score (KSS). Results Eight people were excluded from the study. After the exclusion, the study enrolled 47 patients in the neutral group and 45 patients in the deviant group and were followed for up to 2 years. There was no statistical significance in mean varus angles as well as HKA angle changes during the follow-up phase of each groups (P > 0.05). The mean valgus angles of the patients in the neutral group group were 2.47°, 3.45°, 3.63°, 3.60° and 3.63°, and in the deviation group were 2.45° (P = 0.841), 2.88° (P

Abstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2–Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892–HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.

Abstract Dementia, as an advanced diabetes-associated cognitive dysfunction (DACD), has become the second leading cause of death among diabetes patients. Given that little guidance is currently available to address the DACD process, it is imperative to understand the underlying mechanisms and screen out specific therapeutic targets. The excessive endogenous fructose produced under high glucose conditions can lead to metabolic syndrome and peripheral organ damage. Although generated by the brain, the role of endogenous fructose in the exacerbation of cognitive dysfunction is still unclear. Here, we performed a comprehensive study on leptin receptor-deficient T2DM mice and their littermate m/m mice and revealed that 24-week-old db/db mice had cognitive dysfunction and excessive endogenous fructose metabolism in the hippocampus by multiomics analysis and further experimental validation. We found that the rate-limiting enzyme of fructose metabolism, ketohexokinase, is primarily localized in microglia. It is upregulated in the hippocampus of db/db mice, which enhances mitochondrial damage and reactive oxygen species production by promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression and mitochondrial translocation. Inhibiting fructose metabolism via ketohexokinase depletion reduces microglial activation, leading to the restoration of mitochondrial homeostasis, recovery of structural synaptic plasticity, improvement of CA1 pyramidal neuron electrophysiology and alleviation of cognitive dysfunction. Our findings demonstrated that enhanced endogenous fructose metabolism in microglia plays a dominant role in diabetes-associated cognitive dysfunction and could become a potential target for DACD.

Abstract Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production.

Abstract Prescribing appropriate exercise is an important means to improve the safety and efficacy of cardiac rehabilitation. Improper exercise may induce an increased cardiovascular risk in older persons with coronary heart disease. Cardiopulmonary exercise testing (CPET)-guided cardiac rehabilitation could be helpful for providing clinical evidence for cardiac rehabilitation therapy in older persons after percutaneous coronary intervention (PCI). We retrospectively included older persons who underwent PCI and cardiac rehabilitation based on CPET at the Cardiac Rehabilitation Center of Peking University Third Hospital from January 2014 to December 2019. Patients’ baseline and follow-up clinical data were collected. A total of 403 older persons after PCI were included in the study. The mean age was 80.5 ± 4.3. The mean follow-up time was 12 ± 2 months. During the follow-up period, no significant exercise-related adverse events occurred, and the peak oxygen uptake (VO2peak) increased compared with baseline (15.5 ± 3.8 ml/min/kg vs. 17.3 ± 4.1 ml/min/kg). Among the 90 patients (22.2%) without exercise habits at baseline who started regular exercise during follow-up, the improvement in VO2peak was most significant, at 3.2 ± 0.4 ml/min/kg. Cardiac rehabilitation based on CPET improved exercise habits and exercise tolerance in older persons with coronary heart disease after PCI.

For a special geological structure of columnar jointed rock mass (CJRM), its mechanical properties are strongly affected by the columnar joints. To describe the fracture behaviors of CJRM using the basic theories of interface mechanics for composite materials, the interface stresses of the vertical and horizontal joints, which are the two primary joints in the CJRM under triaxial compression, are studied, and their mathematical expressions are derived based on the superposition principle. Based on the obtained interface stresses of the vertical and horizontal joints in the CJRM, the crack initiation of the joint interface in the CJRM is studied using the maximum circumferential stress theory in fracture mechanics. Moreover, based on this investigation, the fracture behaviors of CJRM are analyzed. According to the results of similar material physical model tests for the CJRM, the theoretical study is verified. Finally, the influence of the mechanical parameters of the CJRM on the joint interface stress is discussed comprehensively.

Objective To analyze the basic characteristics of whole blood donors from blood stations before and after the outbreak of COVID-19. Methods After excluding invalid data, data related to the basic characteristics of whole blood donors collected from 26 blood stations in China during 2018 to 2021 were statistically analyzed, including the trend of total whole blood donors, the number of repeated blood donors, the frequency of blood donation, the average age of donors and the recruitment of first-time blood donors. Results Affected by the epidemic, 8 out of 14 indicators were with large variations, accounting for 57%. The overall growth rate of total whole blood donors during the epidemic was higher than before the epidemic (P

Abstract Evidence has linked alterations of the endocannabinoid system with trauma exposure and posttraumatic stress disorder (PTSD). Childbirth-related PTSD symptoms (CB-PTSS) affect about every eighth woman and can negatively influence the entire family. While aetiological models of CB-PTSD include psychological risk factors such as maternal trauma history and negative subjective birth experience (SBE), they lack biological risk indicators. We investigated whether lifetime trauma and CB-PTSS were associated with long-term endocannabinoid concentrations during pregnancy. Further, we tested endocannabinoids as mediators between lifetime trauma and CB-PTSS and whether SBE moderated such mediational paths. Within the prospective cohort study DREAMHAIR, 263 expectant mothers completed trauma assessments and provided hair samples for quantification of long-term endocannabinoid levels (anandamide [AEA], 2-arachidonoylglycerol [1-AG/2-AG], and N-acyl-ethanolamides [NAE]) prior to their anticipated birth date. Two months postpartum, CB-PTSS and SBE were measured. Regression models controlling for relevant confounders showed no association between lifetime trauma and hair endocannabinoids during pregnancy, yet higher number of lifetime trauma events and lower hair AEA were significantly associated with CB-PTSS, with the latter finding not remaining significant when Bonferroni corrections due to multiple testing were applied. While hair AEA did not mediate the association between lifetime trauma and CB-PTSS, the effect of lower hair AEA on CB-PTSS was stronger upon negative SBE. Results suggest greater lifetime trauma and reduced maternal hair AEA during pregnancy may be associated with increased risk for CB-PTSS, particularly upon negative SBE. Findings confirm lifetime trauma as a CB-PTSS risk factor and add important preliminary insights on the role of endocannabinoid ligand alterations and SBE in CB-PTSS pathology.

In order to explore the influence of dressing process parameters, such as dressing depth ad, axial feed speed fd and dressing speed ratio qd, on the grinding surface integrity of 18CrNiMo7-6 gear steel, orthogonal experiments were conducted for shaping dressing process using ceramic bonded chrome corundum grinding wheels with resin bonded diamond disc wheels, bronze bonded diamond disc wheels and single particle diamond pens, respectively. The cross grinding test of 18CrNiMo7-6 gear steel was carried out with a chrome corundum wheel after dressing. The results show that the surface roughness Ra of the grinding process increased with the increase of the dressing process parameters, and residual compressive stresses were more easily obtained on the grinding surface. The comprehensive evaluation of the grinding surface integrity for the three dressing tools, using a normalized dimensionless method, shows that the grinding surface integrity of the bronze-bonded diamond disc wheel dressing is better than the other two dressing methods. Furthermore, the grinding surface integrity is better when ad=4 μm, fd=100 mm/min, and qd=0.3.

Cercospora apii is an important seedborne pathogenic fungus causing severe Cercospora leaf spot of celery worldwide. Here, we first present a complete genome assembly of C. apii QCYBC from celery, based on Illumina paired-end and PacBio long-read sequencing data. The high-quality genome assembly contains 34 scaffolds with a 34.81 Mb genome size, 330 interspersed repeat genes, 114 noncoding RNAs, and 12,631 protein-coding genes. The benchmarking universal single-copy ortholog (BUSCO) analysis indicated that 98.2% of the BUSCOs were complete, whereas 0.3, 0.7, and 1.1% were duplicated, fragmented, and missing, respectively. Based on annotation, 508 carbohydrate-active enzymes, 243 cytochromes P450 enzymes, 1,639 translocators, 1,358 transmembrane proteins, and 1,146 virulence genes were identified. This genome sequence provides a valuable reference for future studies to improve understanding of the C. apii–celery pathosystem. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF). Methods We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing