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Abstract Objective To compare the impact of telerehabilitation versus conventional rehabilitation on the recovery outcomes of patients with chronic respiratory disease (CRD). Methods The Cochrane Library, MEDLINE, Web of Science and Embase were searched to collect randomized controlled trials (RCTs) on telerehabilitation for the rehabilitation of patients with chronic respiratory system diseases since the establishment of the database to November 14, 2023. Two researchers independently screened the literature and extracted valid data according to the inclusion criteria. The quality assessment of included studies was conducted individually by using the RoB 2(Risk of Bias 2) tool, followed by meta-analysis using RevMan5.3 software. Results Based on inclusion and exclusion criteria, 21 RCTs were included, comprising 3030 participants, with 1509 in the telerehabilitation group and 1521 in the conventional rehabilitation group. Meta-analysis results indicated that compared to conventional rehabilitation, video conference-based telerehabilitation demonstrated significant improvements in short-term (≤ 6 months) outcomes, including 6-min walk distance (6MWD) (MD = 7.52, 95% CI: 2.09, 12.94), modified Medical Research Council Dyspnea Scale (mMRC) (MD = -0.29, 95% CI: -0.41, -0.18), COPD assessment test (CAT) (MD = -1.77, 95% CI: -3.52, -0.02), HADS (MD = -0.44, 95% CI: -0.86, -0.03), and St. George’s Respiratory Questionnaire (SGRQ’s) activity, impact, and symptom scores. In the long term (> 6 months), although improvements persisted in 6WMD [MD = 12.89, 95% CI (-0.37, 26.14)], mMRC [MD = -0.38, 95% CI (-0.56, -0.21)], CAT [MD = -1.39, 95% CI (-3.83, 1.05)], Hospital anxiety and depression scale (HADS) [MD = -0.34, 95% CI (-0.66, -0.03)], and SGRQ’s Activity, Impact, and Symptom scores between intervention and control groups, statistically significant differences were observed only for mMRC and HADS. Without considering time factors, the intervention group exhibited some improvement in FEV1% predicted and the forced expiratory volume in the first one second (FEV1)/ forced vital capacity (FVC) (%) without statistical significance compared to the control group. Conclusion Telerehabilitation therapy demonstrates short-term benefits in enhancing patients’ daily activity capacity, improving respiratory function, and enhancing mental health status, thereby improving patients’ quality of life. However, further high-quality, large-sample RCTs are required to ascertain its long-term effectiveness conclusively. Trial registration This study protocol was approved and registered in PROSPERO: CRD 42024509154.

Abstract The synthesis of constrained 12-membered rings is notably difficult. The main challenges result from constraints during the linear peptide cyclization. Attempts to overcome constraints through excessive activation frequently cause peptidyl epimerization, while insufficient activation of the C-terminus hampers cyclization and promotes intermolecular oligomer formation. We present a β-thiolactone framework that enables the synthesis of cyclo-tetrapeptides via direct aminolysis. This tactic utilizes a mechanism that restricts C-terminal carbonyl rotation while maintaining high reactivity, thereby enabling efficient head-to-tail amidation, reducing oligomerization, and preventing epimerization. A broad range of challenging cyclo-tetrapeptides ( > 20 examples) are synthesized in buffer and exhibits excellent tolerance toward nearly all proteinogenic amino acids. Previously unattainable macrocycles, such as cyclo-L-(Pro-Tyr-Pro-Val), have been produced and identified as μ-opioid receptor (MOR) agonists, with an EC50 value of 2.5 nM. Non-epimerizable direct aminolysis offers a practical solution for constrained peptide cyclization, and the discovery of MOR agonist activity highlights the importance of overcoming synthetic challenges for therapeutic development.

Abstract Ferroptosis, a type of iron-dependent non-apoptotic cell death, plays a vital role in both tumor proliferation and resistance to chemotherapy. Here, our study demonstrates that MAX’s Next Tango (MNT), by involving itself in the spermidine/spermine N1-acetyltransferase 1 (SAT1)-related ferroptosis pathway, promotes the proliferation of lung adenocarcinoma (LUAD) cells and diminishes their sensitivity to chemotherapy. Initially, an RNA-sequence screen of LUAD cells treated with ferroptosis inducers (FINs) reveals a significant increase in MNT expression, suggesting a potential link between MNT and ferroptosis. Overexpression of MNT in LUAD cells hinders changes associated with ferroptosis. Moreover, the upregulation of MNT promotes cell proliferation and suppresses chemotherapy sensitivity, while the knockdown of MNT has the opposite effect. Through the intersection of ChIP-Seq and ferroptosis-associated gene sets, and validation by qPCR and western blot, SAT1 is identified as a potential target of MNT. Subsequently, we demonstrate that MNT binds to the promoter sequence of SAT1 and suppresses its transcription by ChIP-qPCR and dual luciferase assays. Restoration of SAT1 levels antagonizes the efficacy of MNT to inhibit ferroptosis and chemosensitivity and promote cell growth in vitro as well as in vivo. In the clinical context, MNT expression is elevated in LUAD and is inversely connected with SAT1 expression. High MNT expression is also associated with poor patient survival. Our research reveals that MNT inhibits ferroptosis, and impairing chemotherapy effectiveness of LUAD.

Objective Given the distinct physiological and societal traits between women and men, we propose that there are distinct risk factors for lumbar degenerative disc disease surgeries, including lumbar disc herniation (LDH) and lumbar spinal stenosis (LSS), in middle‐aged and older populations. However, few studies have focused on middle‐aged and older women. This study aims to identify these risk factors specifically in this population. Methods In this case–control study, the study group comprised 1202 women aged ≥ 45 years who underwent operative treatment of lumbar degenerative disc disease (LDH, n = 825; LSS, n = 377), and the control group comprised 1168 women without lumbar disease who visited a health examination clinic during the same period. The study factors included demographics (age, body mass index [BMI], smoking, labor intensity, and genetic history), female‐specific factors (menopausal status, number of deliveries, cesarean section, and simple hysterectomy), surgical history (number of abdominal surgeries, hip joint surgery, knee joint surgery, and thyroidectomy), and systemic diseases (hypercholesterolemia, hypertriglyceridemia, hyper‐low‐density lipoprotein cholesterolemia, hypertension, diabetes, cardiovascular disease, and cerebrovascular disease). Multivariate binary logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) of associated factors. Results The risk factors for surgical treatment of LDH in middle‐aged and older women included BMI (OR = 1.603), labor intensity (OR = 1.189), genetic history (OR = 2.212), number of deliveries (OR = 1.736), simple hysterectomy (OR = 2.511), hypertriglyceridemia (OR = 1.932), and hyper‐low‐density lipoprotein cholesterolemia (OR = 2.662). For surgical treatment of LSS, the risk factors were age (OR = 1.889), BMI (OR = 1.671), genetic history (OR = 2.134), number of deliveries (OR = 2.962), simple hysterectomy (OR = 1.968), knee joint surgery (OR = 2.527), hypertriglyceridemia (OR = 1.476), hyper‐low‐density lipoprotein cholesterolemia (OR = 2.413), and diabetes (OR = 1.643). Cerebrovascular disease was a protective factor against surgery for LDH (OR = 0.267). Conclusions BMI, genetic history, number of deliveries, simple hysterectomy, hypertriglyceridemia, and hyper‐low‐density lipoprotein cholesterolemia were independent risk factors for surgical treatment of both LDH and LSS in middle‐aged and older women. Two disparities were found: labor intensity was a risk factor for LDH patients, and knee joint surgery and diabetes were risk factors for LSS patients.

Soybean is an important oil crop and cash crop in China, which not only guarantees people's living needs, but also provides more choices for local agricultural production and creates considerable economic benefits for farmers. Pesticide residue, heavy metal pollution, mycotoxin pollution and plasticizer pollution are the main quality and safety risks in soybean and its products. The present situation of the main pollutants in soybean and its products is summarized in this paper. It points out the possible quality and safety problems of soybean and its products, and puts forward the corresponding control measures to ensure the quality and safety of soybean and its products, in order to provide some thinking and reference for the healthy and rapid development of China's soybean industry.

During the storage and transportation of grapes after picking, diseases occurs generally, including gray mold, aspergillus rot, rhizopus rot, penicillium rot, etc., which seriously affect its production and commodity value. At present, the control of postharvest diseases of grape still depends on chemical control. Long-term application of chemical fungicides can lead to pesticide residues, environmental pollution, harm to human health, and enhance the drug resistance of pathogenic fungal. Using antagonistic bacteria to control postharvest diseases of grape is a green, environmental and safe method instead of chemical fungicides. In this paper, the postharvest infection diseases and symptoms of grape, the source, application effect and their mechanism of action of antagonistic bacteria, the combination of antagonists with other methods to enhance the biocontrol effect are introduced. The prospect of controlling postharvest diseases of grape by antagonistic bacteria is also discussed.

Abstract The unearthed Han Dynasty portrait stones are an important part of China’s ancient artistic heritage, and detecting human images in these stones is a critical prerequisite for studying their artistic value. However, high-precision target detection techniques often result in a large number of parameters, making them unsuitable for portable devices. In this work, we propose a new human image target detection model based on an enhanced YOLO-v5. We discovered that the complex backgrounds, dense group targets, and significant scale variations of targets within large scenes in portrait stones present significant challenges for human target image detection. Therefore, we first incorporated the SPD-Conv convolution and Coordinate Attention self-attention mechanism modules into the YOLO-v5 architecture, aiming to enhance the model’s recognition precision for small target images within Han portrait stones and strengthen its resistance to background disturbances. Moreover, we introduce DIoU NMS and Alpha-IoU Loss to improve the detector’s performance in dense target scenarios, reducing the omission of densely packed objects. Finally, the experimental results from our collected dataset of Han Dynasty stone figure images demonstrate that our method achieves fast convergence and high recognition accuracy. This approach can be better applied to the target detection tasks of special character images in complex backgrounds.

Background/Aims Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Abstract In the post-pandemic era, there is a need for medical professionals with creativity, clinical expertise, and social responsibility. The Chinese government issued a directive to enhance the “Five Characteristics” perceptions of medical students, incorporating moral integrity and adeptness in saving lives and aiding the injured, embracing a compassionate approach to medical practice, possessing the knowledge essential for academic distinction, mastering technical expertise, and the artistry of applying scientific methodologies. The purpose of this study was to investigate the opinions related to ethics and professional behaviors of medical students at one Chinese medical school using a validated 19-item survey instrument and analyze its influencing factors. We conducted a survey in a medical university in Anhui Province, China, and collected 1966 valid questionnaires using the “Five Characteristics Rating Scale”. The results indicated high perceptions of “Five Characteristics” among Chinese medical students (85.42 ± 8.727). Lower-grade-year medical students (86.59 ± 7.888) had higher “Five Characteristics” perceptions than upper-grade-year medical students (84.29 ± 9.327, P

Abstract AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.

Abstract Ruzotolimod (Toll‐like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno‐modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug‐related adverse events of flu‐like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu‐like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC‐suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu‐like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu‐like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN‐α, neopterin, IP‐10, and the transcriptional expression of ISG15, OAS‐1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu‐like symptoms occurrence increases with PD responses (IFN‐α and IP‐10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug‐related flu‐like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu‐like symptoms.

Home battery energy storage systems (HBESSs) has been experiencing an increasingly popularization and marketing process. This consequentially leads to an information filtering challenge for the residential customer to choose the most suitable HBESS products from the large number of candidates HBESSs in the market. This paper proposes a novel personalized HBESS recommender system to provide decision-making support for residential customers to make HBESS choice. The system makes HBESS recommendation following 2 stages: (1) in the first stage, the system uses a federated learning process to aggregately analyze the customers’ preference tendencies on HBESS products from the datasets owned by different HBESS service providers without having the data actually exchanged; based on the learnt preference trends, the system generates a HBESS shortlist that are likely to fit the target customer’s profile; and (2) in the second stage, the system further filters the shortlisted HBESSs by evaluating the household energy cost they can create for the target customer. Combining the considerations of both personal preference and energy cost, several HBESS products are finally selected from the previously generated shortlist and recommended to the target customer. Extensive simulations are conducted to validate the effectiveness of the proposed system.

Background and aimsHepatic perivascular epithelioid cell tumor (PEComa) is a rare type of mesenchymal neoplasm and lacks systematic reports. The aim was to analyze the features of hepatic PEComa in order to provide our own experience for diagnosis and management from a single center.MethodsWe retrospectively analyzed clinical data, imaging findings, pathology, treatments and prognosis of 36 patients with hepatic PEComa in the First Affiliated Hospital of Zhengzhou University from January 2016 to September 2023.Results29 females and 7 males (median age, 47.8 years) were included in this study. The majority (26/36, 72.2%) of patients were diagnosed incidentally with non-specific symptoms. Abnormal enhancement of enlarged blood vessels (27/36,75%) can be observed on CT/MRI and only 7 patients (19.4%) were correctly diagnosed by imaging examinations. The positive immunohistochemical expressions were HMB-45(35/36,97.2%), Melan-A (34/35,97.1%), SMA (23/26,88.5%) and CD34(86.7%,26/30). Treatments include resection (24/36,67.7%), radiofrequency ablation (6/36,16.7%), transcatheter arterial chemoembolization(1/36,2.7%), conservative clinical follow-up(2/36,5.6%), and sirolimus-chemotherapy (3/36,8.3%). During the follow-up period (range, 2–81 months), except for one patient with a single intrahepatic recurrence and 3 malignant patients died in 6 months, the remaining patients had no signs of recurrence and metastasis.ConclusionsHepatic PEComa has no specific clinical features and mainly depends on clinicopathological characteristics for accurate diagnosis. Resection is the best treatment for benign PEComa, but TACE and radiofrequency ablation can also be considered in case of contraindications for surgery.

BackgroundAlthough neoadjuvant therapy has brought numerous benefits to patients, not all patients can benefit from it. Chemokines play a crucial role in the tumor microenvironment and are closely associated with the prognosis and treatment of colorectal cancer. Therefore, constructing a prognostic model based on chemokines will help risk stratification and providing a reference for the personalized treatment.MethodsEmploying LASSO-Cox predictive modeling, a chemokine-based prognostic model was formulated, harnessing the data from TCGA and GEO databases. Then, our exploration focused on the correlation between the chemokine signature and elements such as the immune landscape, somatic mutations, copy number variations, and drug sensitivity. CXCL10+M1 macrophages identified via scRNA-seq. Monocle2 showed cell pseudotime trajectories, CellChat characterized intercellular communication. CytoTRACE analyzed neoadjuvant therapy stemness, SCENIC detected cell type-specific regulation. Lastly, validation was performed through multiplex immunofluorescence experiments.ResultsA model based on 15 chemokines was constructed and validated. High-risk scores correlated with poorer prognosis and advanced TNM and clinical stages. Individuals presenting elevated risk scores demonstrated an increased propensity towards the development of chemotherapy resistance. Subsequent scRNA-seq data analysis indicated that patients with higher presence of CXCL10+ M1 macrophages in tumor tissues are more likely to benefit from neoadjuvant therapy.ConclusionWe developed a chemokine-based prognostic model by integrating both single-cell and bulk RNA-seq data. Furthermore, we revealed epithelial cell heterogeneity in neoadjuvant outcomes and identified CXCL10+ M1 macrophages as potential therapy response predictors. These findings could significantly contribute to risk stratification and serve as a key guide for the advancement of personalized therapeutic approaches.

ABSTRACT: The Jinling White duck represents a newly developed breed characterized by a rapid growth rate and a superior meat quality, offering significant economic value and research potential; however, the genetic basis underlying their body weight traits remains less understood. Here, we performed whole-genome resequencing for 201 diverse Jinling White male ducks and conducted population genomic analyses, suggesting a rich genetic diversity within the Jinling White duck population. Equipped with our genomic resources, we applied genome-wide association analysis for body weight on birth (BWB), body weight on 1 wk (BW1), body weight on 3 wk (BW3), body weight on 5 wk (BW5) and body weight on 7 wk (BW7) using 4 statistical models. Comparative studies indicated that factored spectrally transformed linear mixed models (FaST-LMM) demonstrated the most superior efficiency, yielding more results with the minimal false positives. We discovered that PUS7, FBXO11, FOXN2, MSH6, and SLC4A4 were associated with BWB. RAG2, and TMEFF2 were candidate genes for BW1, and STARD13, Klotho, ZAR1L are likely candidates for BW3 and BW5. PLXNC1, ATP1A1, CD58, FRYL, OCIAD1, and OCIAD2 were linked to BW7. These findings provide a genetic reference for the selection and breeding of Jinling White ducks, while also deepened our understanding of Growth and development phenotypic in ducks.

ObjectiveSelenium is an essential micronutrient and a type of dietary antioxidant. This study aimed to investigate the associations of dietary selenium intake with the risk of human chronic disease [cardiovascular disease (CVD), diabetes mellitus (DM), and cancer] and mortality among US general adults.MethodsThe dietary and demographic data in this study were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Death outcomes were determined by associating with the National Death Index (NDI) records as of December 31, 2019. Logistic regression analyses were used to investigate the relationship of selenium intake with the risk of CVD, DM, and cancer. The effect of dietary selenium on all-cause and disease-specific mortality was estimated with restricted cubic spline (RCS) curves based on the univariate and multivariate Cox proportional hazard models.ResultsAmong the 25,801 participants, dietary selenium intake was divided into quintiles (Q1–Q5). After covariate adjustment, the results showed that the participants with higher quintiles (Q4 and Q5) of selenium intake tended to have a low risk of CVD (OR = 0.97, 95% CI: 0.96, 0.99; OR = 0.98, 95% CI: 0.97, 1.00, respectively). Moreover, the RCS curves showed a significant nonlinear association between selenium intake and the risk of all-cause (with a HR of 0.82, 95% CI: 0.68, 0.99) and DM-specific mortality (with the lowest HR of 0.30; 95% CI, 0.12–0.75). Furthermore, we conducted a subgroup analysis and found a negative correlation between the highest quartile of selenium intake and all-cause mortality among participants aged 50 and above (HR = 0.75, 95% CI: 0.60–0.93, p = 0.009).ConclusionOur results indicated that a moderate dietary selenium supplement decreased the risk of CVD and displayed a nonlinear trend in association with the risk of all-cause and DM-specific mortality among US adults. In addition, we found that participants aged 50 and older may benefit from higher selenium intake. However, these findings still need to be confirmed through further mechanism exploration.

Messenger ribonucleic acid (mRNA) has emerged as a promising molecular preventive and therapeutic approach that opens new avenues for healthcare. Although the use of delivery systems, especially lipid nanoparticles (LNPs), greatly improves the efficiency and stability of mRNA, mRNA tends to accumulate in the liver and hardly penetrates physiological barriers to reach the target site after intravenous injection. Hence, the rational design of targeting strategies aimed at directing mRNA to specific tissues and cells remains an enormous challenge in mRNA therapy. High-throughput screening (HTS) is a cutting-edge targeted technique capable of synthesizing chemical compound libraries for the large-scale experiments to validate the efficiency of mRNA delivery system. In this review, we firstly provide an overview of conventional low-throughput targeting strategies. Then the latest advancements in HTS techniques for mRNA targeted delivery, encompassing optimizing structures of large-scale delivery vehicles and developing large-scale surface ligands, as well as the applications of HTS techniques in extrahepatic systemic diseases are comprehensively summarized. Moreover, we illustrate the selection of administration routes for targeted mRNA delivery. Finally, challenges in the field and potential solutions to tackle them are proposed, offering insights for future development toward mRNA targeted therapy.

Abstract Gut microbiota and their metabolic products might play important roles in regulating the pathogenesis of autism spectrum disorder (ASD). The purpose of this study was to characterize gut microbiota and serum amino acid metabolome profiles in children with ASD. A non-randomized controlled study was carried out to analyze the alterations in the intestinal microbiota and their metabolites in patients with ASD (n = 30) compared with neurotypical controls (NC) (n = 30) by metagenomic sequencing to define the gut microbiota community and liquid chromatography/mass spectrometry (LC/MS) analysis to characterize the metabolite profiles. Compared with children in the NC group, those in the ASD group showed lower richness, higher evenness, and an altered microbial community structure. At the class level, Deinococci and Holophagae were significantly lower in children with ASD compared with TD. At the phylum level, Deinococcus-Thermus was significantly lower in children with ASD compared with TD. In addition, the functional properties (such as galactose metabolism) displayed significant differences between the ASD and NC groups. Five dominant altered species were identified and analyzed (LDA score > 2.0, P

As the amount of new energy injected into the power system increases, the system inertia decreases and the spatio-temporal characteristics become apparent. Due to the uneven distribution of inertia in the power system, the dispersion of the frequency response after disturbance is more pronounced, and the inertia estimation error has a random nature when different frequency measurement points are selected. For the above problems, a method is proposed to select the frequency measurement point based on the centre of inertia. Firstly, based on the frequency dynamic response characteristics, the main influencing factors of the frequency distribution characteristics are studied and the spatial and temporal distribution characteristics of the frequency of the new energy power system are analyzed. Secondly, the method of frequency sampling through the centre of inertia is proposed with full consideration of the electrical distance and generator inertia constants. Finally, a 10 machine 39 bus system is simulated as an example. Simulation results show that using the centre of inertia as the frequency sampling point during inertia evaluation can reduce the inertia evaluation error by up to 16.15%. The results verify the correctness of the above theoretical analysis and provide a favourable basis for further improving the accuracy of the power system inertia estimation.

Abstract Rice (Oryza sativa L.) is the most important food crop worldwide, and its sustainable development is essential to ensure global food security. Panicle morphological and physiological characteristics plays an important role in rice yield formation. However, under different nitrogen (N) fertilization strategies, it is not clear whether the morphological and physiological state of panicles at panicle development stage affects the formation of yield. To understand how the panicle differentiation and development, and grain yield are affected by the N fertilization strategies, and clarify the relationship between related traits and yield in the process of panicle development in different cultivars. In this study consisted of no N fertilizer and four N fertilization strategies, a panicle weight type (PWT) rice cultivar, Dongfu 114 (DF114) and a panicle number type (PNT) rice cultivar, Longdao 11 (LD11) were grown in the field. The results showed that N fertilization strategies could improve the nitrogen use efficiency and yield of rice, but the response of different rice varieties to N fertilizer strategies was different. Different from the DF114, the further increase of panicle N fertilizer ratio could not further improve the yield of LD11, and the highest grain yield of DF114 and LD11 was obtained under N4 and N3 conditions, respectively. In addition, this study found that N fertilizer strategies can affect the content of phytohormones in rice at the panicle differentiation stage, and then regulate the differentiation and development of rice panicles to affect yield. It is of great significance to optimize the application mode of N fertilizer according to the characteristics of varieties to improve rice yield and ensure food security.

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend

Abstract Background Human leucocyte antigen (HLA)-DR plays a crucial role in the immune response against hepatitis B virus (HBV). We aimed to investigate the associations of HLA-DR single nucleotide polymorphisms (SNPs) with the generation of hepatocellular carcinoma (HCC)-related HBV mutations. The effects of HLA-DR SNPs and their interactions with HBV mutations on HCC risks were also determined. Methods Five HLA-DR SNPs (rs3135363, rs9268644, rs35445101, rs24755213, and rs984778) were genotyped in 792 healthy controls, 586 chronic hepatitis B (CHB) patients, 536 liver cirrhosis (LC) patients, and 1500 HCC patients using quantitative PCR. Sanger sequencing was used to identify the HBV mutations. Logistic regression model was performed to evaluate the association of HLA-DR SNPs with HCC risk and the frequencies of HCC-related HBV mutations. Results The variant genotypes at rs3135363, rs9268644, rs35445101, rs24755213, and rs984778 were associated with decreased HCC risks. In genotype C HBV-infected subjects, variant genotypes of these SNPs were associated with decreased frequencies of HCC-related HBV mutations such as C1653T, T1674C/G, G1719T, T1753A/C, A1762T/G1764A, A1846T, G1896A, G1899A, and preS deletion. AG genotype at rs3135363, CA genotype at rs9268644, and AG genotype at rs24755213 reduced the generation of T1753A/C and G1896A in genotype B HBV-infected subjects, respectively. In addition, the interactions of rs3135363, rs9268644, rs24755213 with C1653T, T1753A/C, A1846T, and G1896A decreased the risks of HCC. Conclusions HLA-DR genetic polymorphisms might predispose the host to immunoselection of HCC-related HBV mutations and affect the HCC risks possibly through interacting with HBV mutations.

A quantitative evaluation model that integrates kerogen adsorption and clay pore adsorption of shale oil was proposed, and the evaluation charts of adsorption-swelling capacity of kerogen (Mk) and adsorbed oil capacity of clay minerals (Mc) were established, taking the 1st member of Cretaceous Qingshankou Formation in the northern Songliao Basin as an example. The model and charts were derived from swelling oil experiments performed on naturally evolved kerogens and adsorbed oil experiments on clays (separated from shale core samples). They were constructed on the basis of clarifying the control law of kerogen maturity evolution on its adsorption-swelling capacity, and considering the effect of both the clay pore surface area that occupied by adsorbed oil and formation temperature. The results are obtained in four aspects: (1) For the Qing 1 Member shale, with the increase of maturity, Mk decreases. Given Ro of 0.83%–1.65%, Mk is about 50–250 mg/g. (2) The clay in shale adsorbs asphaltene. Mc is 0.63 mg/m2, and about 15% of the clay pore surface is occupied by adsorbed oil. (3) In the low to medium maturity stages, the shale oil adsorption is controlled by organic matter. When Ro>1.3%, the shale oil adsorption capacity is contributed by clay pores. (4) The oil adsorption capacity evaluated on the surface at room temperature is 8%–22% (avg. 15%) higher than that is held in the formations. The proposed evaluation model reveals the occurrence mechanisms of shale oils with different maturities, and provides a new insight for estimating the reserves of shale oil under formation temperature conditions.

Powder metallurgy (PM) technology is extensively employed in the manufacturing sector, yet its processing presents numerous challenges. To alleviate these difficulties, green machining of PM green compacts has emerged as an effective approach. The aim of this research is to explore the deformation features of green compacts and assess the impact of various machining parameters on the force of cutting. The cutting variables for compacts of PM green were modeled, and the cutting process was analyzed using Abaqus (2022) software. Subsequently, the orthogonal test ANOVA method was utilized to evaluate the significance of each parameter for the cutting force. Optimization of the machining parameters was then achieved through a genetic algorithm for neural network optimization. The investigation revealed that PM green compacts, which are brittle, undergo a plastic deformation stage during cutting and deviate from the traditional model for brittle materials. The findings indicate that cutting thickness exerts the most substantial influence on the cutting force, whereas the speed of cutting, the tool rake angle, and the radius of the rounded edge exert minimal influence. The optimal parameter combination for the cutting of PM green compacts was determined via a genetic algorithm for neural network optimization, yielding a cutting force of 174.998 N at a cutting thickness of 0.15 mm, a cutting speed of 20 m/min, a tool rake angle of 10°, and a radius of the rounded edge of 25 μm, with a discrepancy of 4.05% from the actual measurement.

The objectives of this study were to explore the mechanism of stem mechanical strength in direct-seeded rice (DSR) as affected by paclobutrazol, especially its related endogenous hormone and cell wall component changes in culm tissue and response to the application of paclobutrazol. Field experiments were conducted in Changchun County, Jilin Province, China, by using two japonica rice varieties, Jiyujing and Jijing305, with soaking seeds in paclobutrazol at concentrations of (0 mg L−1, S0; 50 mg L−1; S1; 100 mg L−1; S2; 150 mg L−1, S3; 200 mg L−1, S4) in 2021 and 2022. The results suggest that the application of paclobutrazol increased the grain yield and reduced the lodging rate of DSR. Compared with the S0 treatments, soaking the seeds in paclobutrazol treatments rapidly shortened the length of the basal internode by decreasing the endogenous indole acetic acid (IAA) and gibberellin A3 (GA3) contents in culm tissue. The larger breaking strength (M) was attributed to a higher section modulus (SM) and bending stress (BS). The higher mechanical tissue thickness in culm tissue under paclobutrazol treatments, which was raised by higher endogenous zeatin and zeatin riboside (Z+ZR) content in culm tissue, increased the culm diameter, culm wall thickness, and section modulus (SM) of the internode. Compared with the S0 treatments, soaking the seeds in paclobutrazol treatments increased the cellulose content, lignin content, activities of lignin-related enzymes, and expression of key genes in lignin biosynthesis, as well as resulted in a higher bending stress (BS) to enhance the culm breaking strength (M).

The mechanism by which nitrate inhibits nitrogen fixation in soybean (Glycine max L.) is not fully understood. Accumulation of ureide in soybean plant tissues may regulate the nitrogen fixation capacity through a feedback pathway. In this study, unilaterally nodulated dual-root soybeans prepared by grafting were grown in sand culture. They were subjected to the removal of the nodulated side roots, and were given either nitrate supply or no supply to the non-nodulated side roots for 3 days (experiment I). Additionally, they received nitrate supply to the non-nodulated side roots for 1–14 days (experiment II). The results showed that nitrate supply increased the levels of asparagine and ureide in soybean shoots (Experiment I). In Experiment II, nodule dry weight, nodule number, nodule nitrogenase activity, and nodule urate oxidase activity decreased significantly after 3, 7, and 14 days of nitrate supply. Ureide content in the shoots and nodules increased after 1, 3, and 7 days of nitrate supply, but decreased after 14 days of nitrate supply. There was a significant positive correlation between urate oxidase activity and nitrogenase activity. Hence, we deduced that nitrate supply increased the asparagine content in soybean shoots, likely inhibiting ureide degradation, which induced the accumulation of ureide in soybean shoots and nodules, and, in turn, feedback inhibited the nodule nitrogen fixation. In addition, urate oxidase activity can be used to assess the nitrogen fixation capacity of nodules.

The delay in wound healing caused by chronic wounds or pathological scars is a pressing issue in clinical practice, imposing significant economic and psychological burdens on patients. In particular, with the aging of the population and the increasing incidence of diseases such as diabetes, impaired wound healing is one of the growing health problems. MicroRNA (miRNA) plays a crucial role in wound healing and regulates various biological processes. Our results show that miR–618 was significantly upregulated during the inflammatory phase of wound healing.Subsequently, miR–618 promotes the secretion of pro–inflammatory cytokines and regulates the proliferation and migration of keratinocytes. Mechanistically, miR–618 binds to the target gene–Atp11b and inhibits the PI3K–Akt signaling pathway, inhibiting the epithelial–mesenchymal transition (EMT) of keratinocytes. In addition, the PI3K–Akt signaling pathway induces the enrichment of nuclear miR–618, and miR–618 binds to the promoter of Lin7a to regulate gene transcription. Intradermal injection of miR–618 antagomir around full–thickness wounds in peridermal mice effectively accelerates wound closure compared to control. In conclusion, miR–618 antagomir can be a potential therapeutic agent for wound healing.

The Chinese government has implemented numerous ecological policies in Qinghai Province aimed at protecting and restoring the natural ecosystem. Yet, amid global climate change, the precise effects of these policies on ecological improvement remain ambiguous. There is an urgent need for a comprehensive evaluation of the effects of these policies at a regional scale and an analysis of the changes in policy implementation stages to optimize the strategic direction of regional ecological policies. In this study, using mathematical statistics and spatial analysis, we analysed the spatial and temporal characteristics of the Normalized Difference Vegetation Index (NDVI) in Qinghai Province from 2000 to 2023. Further, by systematically reviewing ten major ecological policies currently or previously implemented in the region, we explored the response of vegetation restoration to these policies through both horizontal and vertical evaluations by reasonably delineating the policy study sub-zones. The study identified distinct stages of policy implementation—regreening, stabilizing, and natural recovery—and correlated these stages with the efficacy of policy impacts. Our findings indicate significant vegetation coverage improvements across Qinghai Province over the past two decades, with all ecological policies positively influencing the environment. The main contribution of this study is that it comprehensively evaluates the impact of multiple ecological policies on vegetation restoration at the regional scale, providing a reference for the formulation and adjustment of subsequent ecological policies.

The limit cycle oscillation (LCO) in the transonic buffet on the fixed supercritical airfoil OAT15A under Ma = 0.73, AoA = 3.5° and Re≈3×106, is successfully simulated by means of the Reynolds Stress Model. Further, the buffet lock-in phenomena under prescribed pitch conditions near the buffet onset are also studied by evaluating the modified energy exchange based on the pitching component of the moment coefficients as well as the normalized relative phase map between the pitching component of the moment coefficients and the airfoil’s angular velocity. The zero energy transfer branches in the modified energy map fail to indicate the lock-in boundaries, while the normalized phase map generally outlines the lock-in boundaries for small pitch amplitudes near the buffet onset, which suggests that the lock-in occurs where the moment is in phase with the angular velocity at small pitch amplitudes near the buffet onset. For pitch amplitudes larger than 0.4°, the lock-in onset deviates from the phase shift, possibly due to the fact the instantaneous angle of attack can be lower than the buffet onset where the buffet phenomena may vanish.

Cuticular waxes are essential for protecting plants from various environmental stresses. Allium fistulosum serves as an excellent model for investigating the regulatory mechanisms underlying cuticular wax synthesis with notable epidermal wax characteristics. A combination of gas chromatography–mass spectrometry (GC–MS) metabolite analysis and transcriptomics was used to investigate variations in metabolites and gene expression patterns between the wild type (WT) and glossy mutant type (gl2) of A. fistulosum. The WT surface had a large number of acicular and lamellar waxy crystals, whereas the leaf surface of gl2 was essentially devoid of waxy crystals. And the results revealed a significant decrease in the content of 16-hentriacontanone, the principal component of cuticular wax, in the gl2 mutant. Transcriptomic analysis revealed 3084 differentially expressed genes (DEGs) between WT and gl2. Moreover, we identified 12 genes related to fatty acid or wax synthesis. Among these, 10 DEGs were associated with positive regulation of wax synthesis, whereas 2 genes exhibited negative regulatory functions. Furthermore, two of these genes were identified as key regulators through weighted gene co-expression network analysis. Notably, the promoter region of AfisC5G01838 (AfCER1-LIKE1) exhibited a 258-bp insertion upstream of the coding region in gl2 and decreased the transcription of the AfCER1-LIKE1 gene. This study provided insights into the molecular mechanisms governing cuticular wax synthesis in A. fistulosum, laying the foundation for future breeding strategies.

IntroductionThe artificial cultivation of morels has been a global research focus owing to production variability. Understanding the microbial ecology in cultivated soil is essential to increase morel yield and alleviate pathogen harm.MethodsA total of nine Morchella cultivation experiments in four soil field types, forest, paddy, greenhouse, and orchard in Shanghai city were performed to determine the potential ecological relationship between Morchella growth and soil microbial ecology.ResultsGenerally, significant variation was observed in the soil microbial diversity and composition between the different experimental field types. The niche width analysis indicated that the bacterial habitat niche breadth was significantly greater than the fungal community width, which was further confirmed by a null model that revealed that homogeneous selection could explain 46.26 and 53.64% of the variance in the bacterial and fungal assemblies, respectively. Moreover, the neutral community model revealed that stochastic processes dominate the bacterial community in forests and paddies and both the bacterial and fungal communities in orchard crops, whereas deterministic processes mostly govern the fungal community in forests and paddies and both the bacterial and the fungal communities in greenhouses. Furthermore, co-occurrence patterns were constructed, and the results demonstrated that the dynamics of the soil microbial community are related to fluctuations in soil physicochemical characteristics, especially soil potassium. Importantly, structural equation modeling further demonstrated that the experimental soil type significantly affects the potassium content of the soil, which can directly or indirectly promote Morchella yield by inhibiting soil fungal richness.DiscussionThis was the first study to predict morel yield through soil potassium fertilizer and soil fungal community richness, which provides new insights into deciphering the importance of microbial ecology in morel agroecosystems.

Summary: Background: Neoadjuvant chemoimmunotherapy has offered novel therapeutic options for patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Depicting the landscape of genomic and immune profiles is critical in predicting therapeutic responses. Methods: We integrated whole-exome sequencing, single-cell RNA sequencing, and immunofluorescence data of ESCC samples from 24 patients who received neoadjuvant treatment with PD-1 inhibitors plus paclitaxel and platinum-based chemotherapy to identify correlations with therapeutic responses. Findings: An elevation of small insertions and deletions was observed in responders. DNA mismatch repair (MMR) pathway alternations were highly frequent in patients with optimal responses and correlated with tumour infiltrating lymphocytes (TILs). Among the TILs in ESCC, dichotomous developing trajectories of B cells were identified, with one lineage differentiating towards LMO2+ germinal centre B cells and another lineage differentiating towards CD55+ memory B cells. While LMO2+ germinal centre B cells were enriched in responding tumours, CD55+ memory B cells were found to correlate with inferior responses to combination therapy, exhibiting immune-regulating features and impeding the cytotoxicity of CD8+ T cells. The comprehensive evaluation of transcriptomic B cell lineage features was validated to predict responses to immunotherapy in patients with cancer. Interpretation: This comprehensive evaluation of tumour MMR pathway alternations and intra-tumoural B cell features will help to improve the selection and management of patients with ESCC to receive neoadjuvant chemoimmunotherapy. Funding: National Science Foundation of China (82373371, 82330053), Eastern Scholar Program at Shanghai Institutions of Higher Learning, National Science and Technology Major Project of China (2023YFA1800204, 2020YFC2008402), and Science and Technology Commission of Shanghai Municipality (22ZR1410700, 20ZR1410800).

ObjectivesThis study aims to investigate the impact of health status and social support on the subjective well-being of older individuals.MethodsUsing data from the China General Social Survey 2017, this research analyzed 5,187 Chinese citizens aged 60 years and older. The predicted effect of each variable on subjective well-being was evaluated through hierarchical regression analysis. The direct and indirect effects of social support and health status on subjective well-being are examined based on a structural equation model.ResultsThe mental health and social support positively impact subjective well-being. Mental health mediates the effect of physical health on subjective well-being, and social support mediates the relationship between physical and mental health and subjective well-being.ConclusionThe findings provide strong evidence for the interrelationship mechanisms among the factors influencing subjective well-being. Consequently, improving mental health services and social support systems is advantageous for enhancing the well-being of Chinese seniors.

Background: The complexity of Chinese medicine treatment for Alzheimer’s disease (AD) utilizing a multi-herb therapy makes the evidence in current studies insufficient. Herb pairs are the most fundamental form of multi-herb formulae. Among the Chinese herbal formulas for AD treatment, Polygala tenuifolia (PT) and Acorus tatarinowii (AT) appeared as the most commonly used herbal pairs in combination.Objective: The aim of this study is to evaluate the clinical efficacy and safety of the combination of PT and AT in the treatment of AD.Methods: We systematically searched and screened randomized controlled trials of pairing PT and AT for the treatment of AD patients in eight databases with a search deadline of June 26, 2023. Authors, year of publication, title, and basic information such as subject characteristics (age, sex, and race), course of disease, control interventions, dose, and treatment duration were extracted from the screened studies. Primary outcomes assessed included mini-mental state examination (MMSE), activities of daily living (ADL), and AD assessment scale-cognitive subscale (ADAS-cog), while secondary outcomes included efficiency and adverse events. The quality of the included studies was assessed using the Cochrane risk of bias tool. The mean difference with 95% confidence intervals (MD [95% CI]) and risk ratio (RR) was selected as the effect size, and the data were analyzed and evaluated using RevMan 5.4 and Stata 16.Results: A total of sixteen eligible and relevant studies involving 1103 AD participants were included. The combination of PT and AT plus conventional drugs was superior to single conventional drugs in MMSE [MD = 2.57, 95%CI: (1.44, 3.69); p < 0.00001; I2 = 86%], ADL [MD = −3.19, 95%CI: (−4.29, −2.09); p < 0.00001; I2 = 0%], and ADAS-cog scores [MD = −2.09, 95%CI: (−3.07, −1.10); p < 0.0001; I2 = 0%]. The combination of PT and AT plus conventional drugs had a significantly more favorable benefit in clinical effectiveness [RR = 1.27, 95%CI: (1.12, 1.44); p = 0.0002; I2 = 0%]. Adverse events were not increased with the combination of PT and AT plus conventional drugs compared to conventional drugs [RR = 0.65, 95%CI: (0.35, 1.19); p = 0.16; I2 = 0%]. The experimental group treated with the combination of PT and AT alone for AD was comparable in MMSE, ADL, and ADAS-cog scores compared with the control group treated with single conventional drugs.Conclusion: Compared to single conventional drugs, the combination of PT and AT may be used as an alternative therapy to improve global cognition and functioning in AD, and the combination of PT and AT as adjunctive therapy appears to produce a better therapeutic response to AD in terms of efficacy without increasing the risk of adverse events. However, the very low to low quality of available evidence limits confidence in the findings.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42023444156.

Glucocorticoids are primary stress hormones that exert neuronal effects via both genomic and non-genomic signaling pathways. However, their rapid non-genomic effects and underlying mechanisms on neural activities remain elusive. In the present study, we investigated the rapid non-genomic effect of glucocorticoids on Kv2.2 channels in cultured HEK293 cells and acute brain slices including cortical pyramidal neurons and calyx-type synapses in the brain stem. We found that cortisol, the endogenous glucocorticoids, rapidly increased Kv2.2 currents by increasing the single-channel open probability in Kv2.2-expressing HEK293 cells through activation of the membrane-associated glucocorticoid receptor. Bovine serum albumin-conjugated dexamethasone, a membrane-impermeable agonist of the glucocorticoid receptor, could mimic the effect of cortisol on Kv2.2 channels. The cortisol-increased Kv2.2 currents were induced by activation of the extracellular signal-regulated protein kinase (ERK) 1/2 kinase, which could be inhibited by U0126, an antagonist of the ERK signaling pathway. In layer 2 cortical pyramidal neurons and the calyx of Held synapses, cortisol suppressed the action potential firing frequency during depolarization and reduced the successful rate upon high-frequency stimulation by activating Kv2.2 channels. We further examined the postsynaptic responses and found that cortisol did not affect the mEPSC and evoked EPSC, but increased the activity-dependent synaptic depression induced by a high-frequency stimulus train. In conclusion, glucocorticoids can rapidly activate Kv2.2 channels through membrane-associated glucocorticoid receptors via the ERK1/2 signaling pathway, suppress presynaptic action potential firing, and inhibit synaptic transmission and plasticity. This may be a universal mechanism of the glucocorticoid-induced non-genomic effects in the central nervous system.

Recently, the rotational Doppler effect has attracted broad attention in detecting rotational motion. However, the presently proposed detection techniques based on the rotational Doppler effect are generally configured relying on discrete components in free space, resulting in cumbersome and inflexible systems, which brings challenges to practical applications. In this paper, we demonstrate a fiber-based configuration on rotational Doppler measurements for the detection of a rotational object using an ultra-broadband mode-selective coupler to convert the superposed vortices. Remarkably, the results show the broadband operating range of the fiber-based measurement system intuitively through wavelength scanning. The refinement of rotational Doppler detection techniques is of great significance for lowering the cost, reducing system complexity, improving system integration, and industrial manufacturing. This fiber-based scheme might be a promising candidate for facilitating the rotational Doppler effect applied as novel motion monitoring and sensing equipment in engineering and industry.

Precipitation is the most common cause of flood. Accurate precipitation prediction is therefore important for flood forecasting and can be a key factor that increases lead time and the accuracy of early flood warning. In this study, the reforecast precipitation of the global ensemble forecast system (GEFS) was postprocessed using CSG EMOS (censored and shifted gamma distribution-based ensemble model output statistics) method to improve its reliability, and then used as the forcing data for Xinanjiang model to increase the lead time of flood forecasts in order to provide a more effective early flood warning based on an empirically water level–discharge curve at Wangjiaba section, Huaihe River basin, China. Three scenarios were set to demonstrate the importance of precipitation prediction in flood forecasting. The results showed that predicted precipitation became more reliable after postprocessing and this improvement increased as lead time expanded. It is also demonstrated that the postprocessed predicted precipitation brings the improvement for flood forecasting, then leads to the gain of early flood warning. However, this improvement becomes less significant by the increase of lead time and fades away when lead time reaches 7 d. In addition, the results of flood forecast and early warning in predicted precipitation scenario were not as good as those in observed precipitation scenario, indicating that substitution of predicted rainfall for observation requires further refinement in future.

Abstract The genus Salvia L. (Lamiaceae) comprises myriad distinct medicinal herbs, with terpenoids as one of their major active chemical groups. Abietane-type diterpenoids (ATDs), such as tanshinones and carnosic acids, are specific to Salvia and exhibit taxonomic chemical diversity among lineages. To elucidate how ATD chemical diversity evolved, we carried out large-scale metabolic and phylogenetic analyses of 71 Salvia species, combined with enzyme function, ancestral sequence and chemical trait reconstruction, and comparative genomics experiments. This integrated approach showed that the lineage-wide ATD diversities in Salvia were induced by differences in the oxidation of the terpenoid skeleton at C-20, which was caused by the functional divergence of the cytochrome P450 subfamily CYP76AK. These findings present a unique pattern of chemical diversity in plants that was shaped by the loss of enzyme activity and associated catalytic pathways.

Oncogene E6 plays a critical role in the development and progression of esophageal cancer caused by human papillomavirus (HPV) infection. Alpha‐ketoglutarate (AKG) is a key metabolite in the tricarboxylic acid cycle and has been widely used as a dietary and anti‐ageing supplement. In this study, we found that treating esophageal squamous carcinoma cells with a high dose of AKG can induce cell pyroptosis. Furthermore, our research confirms that HPV18 E6 inhibits AKG‐induced pyroptosis of esophageal squamous carcinoma cells by lowering P53 expression. P53 downregulates malate dehydrogenase 1 (MDH1) expression; however, MDH1 downregulates L‐2‐hydroxyglutarate (L‐2HG) expression, which inhibits a rise in reactive oxygen species (ROS) levels—as L‐2HG is responsible for excessive ROS. This study reveals the actuating mechanism behind cell pyroptosis of esophageal squamous carcinoma cells induced by high concentrations of AKG, and we posit the molecular pathway via which the HPV E6 oncoprotein inhibits cell pyroptosis.

Abstract RO7062931 is an N‐acetylgalactosamine (GalNAc)‐conjugated single‐stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85‐day follow‐up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment‐related) and seven of eight (87.5%) placebo recipients (n = 1 treatment‐related). Apart from two moderate‐intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection‐related reactions, and headache. Dose‐proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra‐dose‐proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well‐tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first‐in‐human study of RO7062931.

Abstract Background The close relationship between pain and mental health problems is well-known, and psychological intervention can provide an effective alternative to medication-based pain relief. However, previous studies on the connection between pain and psychological problems, the findings thus far have been inconclusive, limiting the potential for translating psychological interventions into clinical practice. To complement the gap, this study utilized genetic data and Mendelian randomization (MR) to examine the potential relationship between pain in different parts and common mental disorders. Methods Based on the instrumental variables selected from the Genome-wide association study summary statistics of localized pain and mental disorders, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between pain and mental disorders. The inverse-variance weighted MR method and MR-Egger were used as the primary statistical method according to the horizontal pleiotropy and heterogeneity level. We reported the odds ratio to infer the causal effect between pain and mental disorders. F statistic was calculated to measure the statistical efficacy of the analyses. Results Insomnia is causally related to the genetic susceptibility of multisite pain including head (OR = 1.09, 95% CI: 1.06–1.12), neck/shoulder (OR = 1.12, 95% CI: 1.07–1.16), back (OR = 1.12, 95% CI: 1.07–1.18) and hip (OR = 1.08, 95% CI: 1.05–1.10). Reversely, headache (OR = 1.14, 95% CI: 1.05–1.24), neck/shoulder pain (OR = 1.95, 95% CI: 1.03–3.68), back pain (OR = 1.40, 95% CI: 1.22–1.60), and hip pain (OR = 2.29, 95% CI: 1.18–4.45) promote the genetic liability of insomnia. Depression is strongly associated with the predisposition of multisite pain including headache (OR = 1.28, 95% CI: 1.08–1.52), neck/shoulder pain (OR = 1.32, 95% CI: 1.16–1.50), back pain (OR = 1.35, 95% CI: 1.10–1.66) and stomach/abdominal pain (OR = 1.14, 95% CI: 1.05–1.25), while headache (OR = 1.06, 95% CI: 1.03–1.08), neck/shoulder (OR = 1.09, 95% CI: 1.01–1.17), back (OR = 1.08, 95% CI: 1.03–1.14), and stomach/abdominal pain (OR = 1.19, 95% CI: 1.11–1.26) are predisposing factors for depression. Additionally, insomnia is associated with the predisposition of facial, stomach/abdominal, and knee pain, anxiety was associated with the predisposition of neck/shoulder and back pain, while the susceptibilities of hip and facial pain are influenced by depression, but these associations were unidirectional. Conclusions Our results enhance the understanding of the complex interplay between pain and mental health and highlight the importance of a holistic approach to pain management that addresses both physical and psychological factors.

Abstract Osteoarthritis (OA) is a prevalent degenerative disease accompanied by the activation of innate and adaptive immune systems-associated inflammatory responses. Due to the local inflammation, the expression of various cytokines was altered in affected joints, including CC motif chemokine ligands (CCLs) and their receptors (CCRs). As essential members of chemokines, CCLs and CCRs played an important role in the pathogenesis and treatment of OA. The bindings between CCLs and CCRs on the chondrocyte membrane promoted chondrocyte apoptosis and the release of multiple matrix-degrading enzymes, which resulted in cartilage degradation. In addition, CCLs and CCRs had chemoattractant functions to attract various immune cells to osteoarthritic joints, further leading to the aggravation of local inflammation. Furthermore, in the nerve endings of joints, CCLs and CCRs, along with several cellular factors, contributed to pain hypersensitivity by releasing neurotransmitters in the spinal cord. Given this family’s diverse and complex functions, targeting the functional network of CCLs and CCRs is a promising strategy for the prognosis and treatment of OA in the future.

Studying drug-target interactions (DTIs) is the foundational and crucial phase in drug discovery. Biochemical experiments, while being the most reliable method for determining drug-target affinity (DTA), are time-consuming and costly, making it challenging to meet the current demands for swift and efficient drug development. Consequently, computational DTA prediction methods have emerged as indispensable tools for this research. In this article, we propose a novel deep learning algorithm named GRA-DTA, for DTA prediction. Specifically, we introduce Bidirectional Gated Recurrent Unit (BiGRU) combined with a soft attention mechanism to learn target representations. We employ Graph Sample and Aggregate (GraphSAGE) to learn drug representation, especially to distinguish the different features of drug and target representations and their dimensional contributions. We merge drug and target representations by an attention neural network (ANN) to learn drug-target pair representations, which are fed into fully connected layers to yield predictive DTA. The experimental results showed that GRA-DTA achieved mean squared error of 0.142 and 0.225 and concordance index reached 0.897 and 0.890 on the benchmark datasets KIBA and Davis, respectively, surpassing the most state-of-the-art DTA prediction algorithms.

Ultra-high-performance concrete (UHPC) with a low steel fiber volume fraction offers lower material costs than UHPC with typical steel fiber volume fractions, and has the potential to mitigate the ductility degradation of rebar-reinforced UHPC (R-UHPC). This study explores the reinforcement effect on the tensile behavior of UHPC with a low fiber volume fraction with the aim of facilitating more cost-efficient UHPC applications. The axial tensile behavior of 30 UHPC specimens with low fiber volume fractions at different reinforcement ratios was tested through direct tensile tests. The findings indicate that adopting UHPC with a low fiber volume fraction can significantly mitigate the ductility deterioration of rebar-reinforced UHPC (R-UHPC), and both increasing the reinforcement ratio and decreasing the fiber volume fraction contribute to the improvement in ductility. The failure modes of R-UHPC are determined by the ratio of reinforcement ratio and fiber volume fraction, rather than a single parameter, which also means that R-UHPC with different parameters may correspond to different methods to predict tensile load-bearing capacity. For UHPC with a fiber volume fraction low to 0.5%, incorporating steel rebars gives superior multi-crack cracking behavior and excellent capacity to restrict the maximum crack width. Increasing the fiber volume fraction from 0.5% to 1.0% at the same reinforcement ratio will yield little benefit other than an increase in tensile load-bearing capacity.

Abstract Background The surgical procedure for laparoscopic right colectomy (LRC) is not standardized. Some published studies show the superiority of ileocolic anastomosis (IIA), but the evidence so far is insufficient. This study aimed to investigate the potential advantages in postoperative recovery and safety of IIA in LRC. Methods A total of 114 patients who underwent LRC with IIA (n = 58) or extracorporeal ileocolic anastomosis (EIA, n = 56) between January 2019 and September 2021 were enrolled. We collected certain factors as clinical features, intraoperative characteristics, oncological outcomes, postoperative recovery, and short-term outcomes. Our primary outcome was time to gastrointestinal (GI) function recovery. Secondary outcomes were postoperative complications within 30 days, postoperative pain, and length of hospital stay. Results Faster GI recovery and less postoperative pain were observed in patients with IIA compared to EIA [time to first flatus: (2.4 ± 0.7) vs (2.8 ± 1.0) days, p

Abstract Background Antibacterial activity and on-demand removability are key characteristics governing the effectiveness of clinic wound dressing. However, the excellent tissue adhesion of new dressings is often overemphasized without a detailed discussion of dressing replacement. Besides, the inherent antibacterial ability of dressings is beneficial for promoting the healing of infected wound. Therefore, we rationally design an injectable antibacterial wound dressing with on-demand removability to accelerate infected wound healing. Method We design this wound dressing with a simple and feasible method based on the electrostatic self-assembly of hyaluronic acid and ε-polylysine. We investigated the efficacy of this dressing in terms of its microtopography, rheology, self-healing performance, adhesive ability, antimicrobial, hemostatic, on-demand removal properties, and wound healing promotion through various tests. Results The prepared dressing possesses injectability, self-healing ability and antibacterial activity, showing NaCl-triggered on-demand dissolution due to the disruption of electrostatic interactions. When used as dressings for healing full-thickness wounds, it could effectively accelerate wound healing by killing bacteria, downregulating inflammation, promoting collagen deposition, enhancing keratinocyte migration and angiogenesis due to its excellent adhesion ability, favorable hemostatic property, and potent antibacterial performance. Conclusion All results indicate that this is a simple and practical dressing for clinical application. This strategy provides a novel idea for developing on-demand removal dressings with antibacterial and injectable properties.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

Abstract Objective The purpose of this study was to develop a scale of clinician training elements in the new period and test its reliability and validity. Methods Our approach was based on interdisciplinary theory, systematology, collaborative innovation theory, and whole person education theory combined with the existing post competency model of Chinese doctors and the responsibilities and requirements endowed clinicians in the new historical period. The scale elements were extracted by referring to the relevant literature, and the training elements scale for clinicians in the new period were preliminarily formed. From July to August 2022, 1,086 clinicians from tertiary medical institutions in eastern, central, and western China were sampled and investigated. The questionnaire was revised via the critical ratio method and homogeneity test method, and the reliability and validity of the scale were also tested. Results The training elements scale for clinicians in the new period included the following eight dimensions: basic clinical knowledge, interdisciplinary knowledge, clinical skill operation, public health knowledge, technological innovation capability, lifelong learning needs, medical humanistic literacy, and international exchange vision, as well as 51 other items. The Cronbach’s α coefficient of the scale was 0.981, the half-reliability was 0.903, and the average variance extraction of each dimension was greater than 0.5. An exploratory factor analysis extracted eight main factors, and the cumulative variance contribution rate was 78.524%. Confirmatory factor analysis showed that the model fit was ideal and the factor structure was stable. Conclusion The clinician training factor scale in the new era can fully meet the current training needs of r clinicians, and has good reliability and validity. It can be widely used in medical colleges and universities as a reference to reform the content of medical training and education, and can also be used in the continuing education of clinicians after graduation to compensate for gaps in knowledge during clinical work.

Abstract Backgroud There were limitations existing in programmed cell‐death ligand 1 (PD‐L1) as predictive biomarkers for breast cancer (BC), hence exploring the correlation between PD‐L1 levels and other biomarkers in BC may become a very useful therapeutic clinical tool. Methods A total of 301 Chinese patients with different BC subtypes including 47 HR+/HER2+, 185 HR+/HER2−, 38 HR−/HER2+, and 31 triple‐negative breast cancer (TNBC) were enrolled in our study. Next‐generation sequencing based Yuansu450 gene panel was used for genomic alteration identification and PD‐L1 expression was tested using immunohistochemistry. Results The most prevalent BC‐related mutations were TP53 mutations, followed by mutations in PIK3CA, ERBB2, CDK12, and GATA3 in our Chinese cohort. We found that mutations DDR2 and MYCL were only mutated in HR−/HER2+ subtype, whereas H3‐3A and NRAS mutations were only occurred in HR−/HER2− subtype. The percentage of patients with PD‐L1‐positive expression was higher in patients with HR‐/HER2− mainly due to the percentage of PD‐L1‐high level. Mutational frequencies of TP53, MYC, FAT4, PBRM1, PREX2 were observed to have significant differences among patients with different BC subtypes based on PD‐L1 levels. Moreover, a positive correlation was observed between TMB and PD‐L1 level in HR+/HER2− subtype, and showed that the proportion of patients with high PD‐L1 expression was higher than that of patients with low PD‐L1 expression in the HR+/HER2− and HR+/HER2+ cohorts with high Ki67 expression. Conclusions The genomic alterations based on PD‐L1 and other biomarkers of different cohorts may provide more possibilities for the treatment of BC with different subtypes.