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Abstract Background Fritillaria ussuriensis is an endangered medicinal plant known for its notable therapeutic properties. Unfortunately, its population has drastically declined due to the destruction of forest habitats. Thus, effectively protecting F. ussuriensis from extinction poses a significant challenge. A profound understanding of its genetic foundation is crucial. To date, research on the complete mitochondrial genome of F. ussuriensis has not yet been reported. Results The complete mitochondrial genome of F. ussuriensis was sequenced and assembled by integrating PacBio and Illumina sequencing technologies, revealing 13 circular chromosomes totaling 737,569 bp with an average GC content of 45.41%. A total of 55 genes were annotated in this mitogenome, including 2 rRNA genes, 12 tRNA genes, and 41 PCGs. The mitochondrial genome of F. ussuriensis contained 192 SSRs and 4,027 dispersed repeats. In the PCGs of F. ussuriensis mitogenome, 90.00% of the RSCU values exceeding 1 exhibited a preference for A-ended or U-ended codons. In addition, 505 RNA editing sites were predicted across these PCGs. Selective pressure analysis suggested negative selection on most PCGs to preserve mitochondrial functionality, as the notable exception of the gene nad3 showed positive selection. Comparison between the mitochondrial and chloroplast genomes of F. ussuriensis revealed 20 homologous fragments totaling 8,954 bp. Nucleotide diversity analysis revealed the variation among genes, and gene atp9 was the most notable. Despite the conservation of GC content, mitogenome sizes varied significantly among six closely related species, and colinear analysis confirmed the lack of conservation in their genomic structures. Phylogenetic analysis indicated a close relationship between F. ussuriensis and Lilium tsingtauense. Conclusions In this study, we sequenced and annotated the mitogenome of F. ussuriensis and compared it with the mitogenomes of other closely related species. In addition to genomic features and evolutionary position, this study also provides valuable genomic resources to further understand and utilize this medicinal plant.

Abstract Background Although several studies have found the relationship between essential elements and diabetes, the studies about the association of essential elements with diabetes diagnosed according to an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) in a sex- and age-specific manner were limited. To investigate the linear and nonlinear relationship of five essential elements including iron (Fe), copper (Cu), Zinc (Zn), magnesium (Mg), and calcium (Ca) with diabetes, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (PPG), and HbA1c and to evaluate the sex- and age-specific heterogeneities in these relationships. Methods A total of 8392 community-dwelling adults were recruited to complete a questionnaire and undergo checkups of anthropometric parameters and serum levels of five metals (Fe, Cu, Zn, Mg, and Ca). The multivariable logistic and linear regression, the restricted cubic spline (RCS) analysis, and subgroup analysis were applied to find the associations between the essential elements and the prevalence of diabetes as well as FPG, PPG, and HbA1c. Results In the multivariable logistic regression and multivariable linear regression, serum Cu was positively associated with FPG, PPG, and HbA1c while serum Mg was significantly inversely correlated with FPG, PPG, HbA1c, and diabetes (all P

Abstract Spatial transcriptomics has transformed our ability to study tissue complexity. However, it remains challenging to accurately dissect tissue organization at single-cell resolution. Here we introduce scHolography, a machine learning-based method designed to reconstruct single-cell spatial neighborhoods and facilitate 3D tissue visualization using spatial and single-cell RNA sequencing data. scHolography employs a high-dimensional transcriptome-to-space projection that infers spatial relationships among cells, defining spatial neighborhoods and enhancing analyses of cell–cell communication. When applied to both human and mouse datasets, scHolography enables quantitative assessments of spatial cell neighborhoods, cell–cell interactions, and tumor-immune microenvironment. Together, scHolography offers a robust computational framework for elucidating 3D tissue organization and analyzing spatial dynamics at the cellular level.

Abstract Background Soybean mosaic disease caused by soybean mosaic virus (SMV) is one of the most devastating and widespread diseases in soybean producing areas worldwide. The WRKY transcription factors (TFs) are widely involved in plant development and stress responses. However, the roles of the GmWRKY TFs in resistance to SMV are largely unclear. Results Here, 185 GmWRKYs were characterized in soybean (Glycine max), among which 60 GmWRKY genes were differentially expressed during SMV infection according to the transcriptome data. The transcriptome data and RT-qPCR results showed that the expression of GmWRKY164 decreased after imidazole treatment and had higher expression levels in the incompatible combination between soybean cultivar variety Jidou 7 and SMV strain N3. Remarkably, the silencing of GmWRKY164 reduced callose deposition and enhanced virus spread during SMV infection. In addition, the transcript levels of the GmGSL7c were dramatically lower upon the silencing of GmWRKY164. Furthermore, EMSA and ChIP-qPCR revealed that GmWRKY164 can directly bind to the promoter of GmGSL7c, which contains the W-box element. Conclusion Our findings suggest that GmWRKY164 plays a positive role in resistance to SMV infection by regulating the expression of GmGSL7c, resulting in the deposition of callose and the inhibition of viral movement, which provides guidance for future studies in understanding virus-resistance mechanisms in soybean.

Abstract Background Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. Methods In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients’ cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients’ depressive symptoms at baseline and week 2. Results After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p

Abstract Cuproptosis is a newly defined form of programmed cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis and metastasis. However, whether cuproptosis-related lncRNAs are involved in the pathogenesis of diffuse large B cell lymphoma (DLBCL) remains unclear. This study aimed to identify the prognostic signatures of cuproptosis-related lncRNAs in DLBCL and investigate their potential molecular functions. RNA-Seq data and clinical information for DLBCL were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Cuproptosis-related lncRNAs were screened out through Pearson correlation analysis. Utilizing univariate Cox, least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analysis, we identified seven cuproptosis-related lncRNAs and developed a risk prediction model to evaluate its prognostic value across multiple groups. GO and KEGG functional analyses, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. Additionally, drug sensitivity analysis identified drugs with potential efficacy in DLBCL. Finally, the protein–protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). We identified a set of seven cuproptosis-related lncRNAs including LINC00294, RNF139-AS1, LINC00654, WWC2-AS2, LINC00661, LINC01165 and LINC01398, based on which we constructed a risk model for DLBCL. The high-risk group was associated with shorter survival time than the low-risk group, and the signature-based risk score demonstrated superior prognostic ability for DLBCL patients compared to traditional clinical features. By analyzing the immune landscapes between two groups, we found that immunosuppressive cell types were significantly increased in high-risk DLBCL group. Moreover, functional enrichment analysis highlighted the association of differentially expressed genes with metabolic, inflammatory and immune-related pathways in DLBCL patients. We also found that the high-risk group showed more sensitivity to vinorelbine and pyrimethamine. A cuproptosis-related lncRNA signature was established to predict the prognosis and provide insights into potential therapeutic strategies for DLBCL patients.

Abstract Introduction Dental implantation has emerged as an efficient substitute for missing teeth, which is essential for restoring oral function and aesthetics. Compared to traditional denture repair approaches, dental implants offer better stability and sustainability. The position, angle, and depth of dental implants are crucial factors for their long-term success and necessitate high-precision operation and technical support. Method We propose an integrated dual-arm high-precision oral implant surgery navigation positioning system and a corresponding control strategy. Compared with traditional implant robots, the integrated dual-arm design greatly shortens the preparation time before surgery and simplifies the operation process. We propose a novel control flow and module for the proposed structure, including an Occluded Target Tracking Module (OTTM) for occlusion tracking, a Planting Plan Development Module (PPDM) for generating implant plans, and a Path Formulation Module (PFM) for controlling the movement path of the two robot arms. Result Under the coordinated control of the aforementioned modules, the robot achieved excellent accuracy in clinical trials. The average angular error and entry point error for five patients who underwent implant surgery using the proposed robot were 2.1° and 0.39 mm, respectively. Conclusion In essence, our study introduces an integrated dual-arm high-precision navigation system for oral implant surgery, resolving issues like lengthy preoperative preparation and static surgical planning. Clinical results confirm its efficacy, emphasizing its accuracy and precision in guiding oral implant procedures.

It is a proven authenticity that probability-schooled methodologies have a cardinal role in making decisions under the vagueness circumstances. Thus, to reach meaningful and fruitful decisions under vagueness circumstances, numerous probability-focused methodologies have been introduced, promoted, and implemented. This paper also contributes to adding another useful probability model to the existing literature for data modeling in engineering-oriented areas. The new model is called the weighted sine exponentiated exponential (WSEE) distribution, which is formed by implementing the exponentiated exponential model together with a sine-adapted method. Certain properties of the WSEE distribution are given. The parameter estimation of the WSEE distribution along with the simulation study is also provided. Last, in order, we apply the WSEE distribution for analyzing three data sets taken from the musical engineering and reliability settings. The optimality of the WSEE distribution is proved by comparing its results with other prominent modifications of the exponentiated exponential distribution. Using 4 statistical criteria as judgment tools, it was shown numerically and pictorially that the WSEE distribution is an optimal and suitable model for the musical engineering reliability data sets.

It is an established and already accomplished fact that probability-based methodologies (or probability/statistical distributions) play the roles of imperative tools in illustrating and describing applied phenomena. Paying attention to these previous facts, this paper considers the evolution of a new probability distribution. Thus, the main achievement of this paper leads to a new probability distribution as a result of combining the exponentiated exponential model with a tangent-based stratagem. The new model is called the tangent exponentiated exponential (TEE) distribution. For the TEE distribution, certain distributional properties and estimators of the model parameters are derived mathematically. The appraisal of the estimators of the TEE distribution is accomplished through a simulation study. Moreover, the applicability and virtuoso of the TEE distribution are exemplified via two data sets, which are taken from the music engineering (named Data 1) and reliability sector (named Data 2). By considering the p-value and three other important statistical tests/methods as diagnostic tools, we find that the TEE distribution is the most useful and optimal model for Data 1 and Data 2 compared to certain candidate probability distributions.

In order to explore the effects of pore size, aromatic lamellar stacking degree, aromatic lamellar ductility, gas temperature and gas pressure on the competitive adsorption of CH4 and CO2, the No.3 coal from Jincheng mining area was taken as the research object. The adsorption process of binary mixed gas of CH4 and CO2 in coal under different temperatures, pressures, pore diameters, aromatic lamellar stacking degrees and aromatic lamellar ductility was studied. The microstructure of coal was tested and analyzed based on industrial analysis and X-ray diffraction experiments. Molecular simulation of the process of gas mixture adsorption in coal using the Grand Canonical Monte Carlo (GCMC) method. The results shown that, the increase of gas pressure was favorable for adsorption, and the adsorption capacity of CO2 was close to saturation at a pressure of 5 MPa. The increase of temperature led to a decrease in the maximum adsorption capacity and adsorption heat of CO2 in coal. The increase of pore size led to the increase of CH4 adsorption capacity in coal, with the fastest increase in CH4 adsorption occurred when pore size increased from 1 nm to 2 nm. With the increase of aromatic lamellar stacking degree, the number of gas molecules adsorbed in coal did not change significantly, but CO2 adsorption capacity of per unit mass in coal decreased rapidly, and the CH4 adsorption capacity decreased slightly. With the increase of aromatic lamellar ductility, the number of CH4 molecules adsorbed in coal increased slowly and the number of CO2 molecules adsorbed increased rapidly, and the change of the two gases adsorption capacity in coal per unit mass was not significant. From the perspective of adsorption capacity and adsorption heat, CO2 is in a dominant position in the competitive adsorption process, so injecting CO2 into coal seam can effectively displace CH4. The results of this paper strengthened the molecular understanding of the adsorption of binary mixed gas of CH4 and CO2, which can lay a theoretical foundation for the enhancement of coalbed methane extraction by CO2 injection.

Abstract Plant cells perceive pathogen invasion by recognizing microbial patterns using plasma-membrane-localized pattern-recognition receptors (PRRs) to initiate pattern-triggered immunity (PTI), which confers a moderate immunity to most microbes. For instance, the PRR FLS2 (FLAGELLIN SENSING 2) recognizes bacterial flagellin in the presence of the co-receptor BAK1 and activates a series of PTI responses, such as reactive oxygen species (ROS) burst and mitogen-activated protein kinase (MAPK) activation. We previously showed that soybean malectin/malectin-like domain-containing receptor-like kinase (MRLK) protein GmLMM1 negatively regulates PTI by suppressing FLS2-BAK1 interaction. GmLMM1 replicates in tandem with five other GmMRLKs on chromosome 13. Here, we show that GmMRLK32, the closest homolog to GmLMM1 among the tandem genes of GmLMM1, negatively regulates PTI and disease resistance against bacterial and oomycete pathogens. The Gmmrlk32 mutant showed enhanced flg22-induced ROS burst and MAPK activation. We revealed that GmMRLK32 interacts with GmFLS2 and GmBAK1, and suppresses flg22-induced GmFLS2-GmBAK1 dimerization in a manner similar to that of GmLMM1. We further showed that GmMRLK32 specifically interacts with GmLMM1 to regulate PTI. In Nicotiana benthamiana plants, co-expression of GmMRLK32 and GmLMM1 showed a stronger PTI inhibitory effect on PTI activation than expression of GmMRLK32 or GmLMM1 alone. We uncovered a novel mechanism by which GmMRLK32 and GmLMM1 coordinately regulate PTI by forming hetero-oligomer.

BackgroundSuicide attempts and anxiety are common commodities in patients with major depressive disorder (MDD), and suicide attempts are often associated with anxiety symptoms. Studies have found gender differences in several aspects of MDD; however, gender differences in suicide attempts in young first-episode and drug-naive (FEDN) MDD patients with anxiety remain unknown. This study aimed to investigate potential gender differences in the prevalence of suicide attempts and associated risk factors among young FEDN MDD patients with anxiety in a Chinese Han population.MethodsA cross-sectional study was conducted on 1289 young patients with FEDN MDD. Demographics, clinical characteristics, and biochemical parameters of patients were collected.ResultsSuicide attempters accounted for 23.80% and 26.12% of male and female FEDN MDD patients with anxiety, respectively, with no significant gender differences. Binary logistic regression analyses showed that anxiety, clinical global impression severity, and thyroid peroxidase antibody significantly predicted suicide attempts in both male and female FEDN MDD patients with anxiety, while body mass index significantly predicted suicide attempts only in males, and psychotic symptoms predicted suicide attempts only in females.ConclusionThe present study represents the first large-scale investigation of gender differences in the prevalence of suicide attempts and related risk factors among young FEND MDD patients with anxiety in the Chinese Han population. The results indicate that risk factors associated with suicide attempts vary by gender among young FEND MDD patients with anxiety, although a comparable rate of suicide attempts was observed in both female and male patients.

Abstract Retinopathy of prematurity (ROP) mainly occurs in premature infants with low birth weight, and it is the leading cause of childhood blindness. Early and accurate ROP diagnosis is imperative for appropriate treatment. However, less research concentrates on early‐stage ROP diagnosis based on limited‐labelled images in an imbalanced dataset. To address the dilemma, this study proposed a novel self‐supervised network, MOCO‐MIM, for early ROP grading. The proposed classification network was evaluated on a total of 553 labelled fundus images from 89 preterm infants. The trained network achieved a test accuracy of 98.29% and an AUC score of 97.6% for three stages of grading. The adopted method is verified that the proposed method can be detected early stages of ROP more efficiently and grade the severity more accurately based on limited‐labelled fundus images, which is superior to the existing state‐of‐the‐art methods.

Summary: Maternal obesity has long-term effects on offspring metabolic health. Among the potential mechanisms, prior research has indicated potential disruptions in circadian rhythms and gut microbiota in the offspring. To challenge this hypothesis, we implemented a maternal high fat diet regimen before and during pregnancy, followed by a standard diet after birth. Our findings confirm that maternal obesity impacts offspring birth weight and glucose and lipid metabolisms. However, we found minimal impact on circadian rhythms and microbiota that are predominantly driven by the feeding/fasting cycle. Notably, maternal obesity altered rhythmic liver gene expression, affecting mitochondrial function and inflammatory response without disrupting the hepatic circadian clock. These changes could be explained by a masculinization of liver gene expression similar to the changes observed in polycystic ovarian syndrome. Intriguingly, such alterations seem to provide the first-generation offspring with a degree of protection against obesity when exposed to a high fat diet.

Summary: Acute myeloid leukemia (AML) is a clonal malignancy originating from leukemia stem cells, characterized by a poor prognosis, underscoring the necessity for novel therapeutic targets and treatment methodologies. This study focuses on Ras homolog family member F, filopodia associated (RHOF), a Rho guanosine triphosphatase (GTPase) family member. We found that RHOF is overexpressed in AML, correlating with an adverse prognosis. Our gain- and loss-of-function experiments revealed that RHOF overexpression enhances proliferation and impedes apoptosis in AML cells in vitro. Conversely, genetic suppression of RHOF markedly reduced the leukemia burden in a human AML xenograft mouse model. Furthermore, we investigated the synergistic effect of RHOF downregulation and chemotherapy, demonstrating significant therapeutic efficacy in vivo. Mechanistically, RHOF activates the AKT/β-catenin signaling pathway, thereby accelerating the progression of AML. Our findings elucidate the pivotal role of RHOF in AML pathogenesis and propose RHOF inhibition as a promising therapeutic approach for AML management.

Flexible sensors show the wide range of applications in electronic products. However, challenges remain in developing sensors with internal complex construction, excellent flexibility, elasticity and strength. In this paper, a prepolymer (PU-PDMS-OH-HEMA) contain polyurethane (PU) segments and polysiloxane (PDMS) segments was synthesized, and the photosensitive resins with low viscosity for 3D printing were prepared by mixing prepolymers with diluents and photoinitiators. The resultant cured photosensitive resins showed the improved mechanical properties. The PDMS-OH-30 sample exhibit the excellent mechanical properties, with tensile strength and elongation at break of 10.03 MPa and 1046.15 %, respectively, and the resin viscosity of 62 cP. Conductive ionic liquids were added to the above photosensitive resins to prepare flexible sensors, which show the electrical sensitivity and stability. The findings in the work propose a contribution to the development of highly flexible 3D printing resins for fabricating flexible sensors.

Summary: Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18–65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin −10% (2.69%; 95% CI −4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (−3.25; 95% CI −5.56, −0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP

Background: This study aimed to examine the associations of thyroid hormone sensitivity indices, including free triiodothyronine-to-free thyroxine (FT3/FT4) ratio, thyroid feedback quantile-based index by FT4 (TFQIFT4), thyroid-stimulating hormone index (TSHI), and thyrotrophic thyroxine resistance index (TT4RI) with all-cause mortality in euthyroid adults. Methods: The study included 6243 euthyroid adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2012. FT3/FT4 ratio, TFQIFT4, TSHI, and TT4RI were calculated. The multivariable Cox proportional hazard regression, restricted cubic spline (RCS), and subgroup analysis were conducted. Results: Individuals in fourth quartile (Q4) had lower all-cause mortality than those in first quartile (Q1) of FT3/FT4 ratio (hazard ratio (HR): 0.70, 95% CI: 0.51, 0.94). Regarding TFQIFT4, individuals in Q4 of TFQIFT4 had a 43% higher all-cause mortality than those in Q1 (HR: 1.43, 95% CI: 1.05, 1.96) (P < 0.05, all). Compared with participants in Q1, no associations of TSHI and TT4RI with mortality were found. TFQIFT4 was linearly and positively associated with mortality. However, the FT3/FT4 ratio showed a U-shaped association with mortality. Conclusions: Increased risk for all-cause mortality was positively associated with TFQIFT4, suggesting that increased risk for all-cause mortality was associated with decreased central sensitivity to thyroid hormones. Furthermore, the FT3/ FT4 ratio showed a U-shaped association with mortality, with an inflection point at 0.5. However, more cohort studies are needed to validate the conclusions.

Abstract Aim This study aimed to undertake a bibliometric analysis to provide comprehensive information in demonstrating the current status and outline the overall trends in the area of readiness for hospital discharge (RHD). Design A bibliometric and visual analysis of RHD literature was undertaken. Methods Articles were retrieved from the Web of Science network from 2002 to 2021. VOSviewer was used to identify the co‐authorship network of countries/institutions, co‐authorship and co‐citation analysis of authors, and co‐citation analysis of references and citation analysis of documents. CiteSpace was used to identify the keyword co‐occurrence network and perform cluster analysis, detecting the keywords with citation bursts and speculated frontiers in this research field. Results A total of 512 articles were included in the final analysis. Key findings are: (1) There has been a continuous but somewhat fluctuating rise in the number of publications. (2) 56.05% of publications come from the USA with Marquette University making the highest contribution. (3) Most publications (17, 3.32%) in RHD research were from the Journal of Clinical Nursing, and Anaesthesia and Analgesia had the highest number of citations (584 citations). (4) Weiss ME (25, 4.88%) was the most productive author whose articles have been the most highly cited (646 citations). (5) Cited references from Weiss ME (2007) also made the largest contribution to co‐citations, and the most cited reference was from Jack BW (2009) (1022 citations). (6) The 20 most frequent keywords and keywords with the strongest citation bursts were retrieved. There were seven research hotspots, and three emerging research frontiers were explored. Conclusions The bibliometric analysis of material published in the last 20 years indicates that there have been statistically significant gains in comprehensive information on RHD, including the knowledge mapping of the countries, institutions, authors, references and keywords. The hotspots and frontiers, which have been explored can give guidance to researchers as to new angles and directions to take. Implications for Nursing Management The effects of the implementation of ERAS on RHD‐related risk for adverse post‐discharge outcomes in surgical patients will be of increasing concern for healthcare professionals. It is important for patients and their relatives to be confident that on discharge they are sufficiently ready for hospital discharge to enable them to safely and smoothly make the transition to home. Improving the level of RHD in discharged patients can help nurse managers and researchers measure the effectiveness of discharge planning services.

BackgroundPrevious studies have revealed the sex-specific features of pituitary–thyroid hormone (TH) actions and the prevalence of thyroid nodules (TNs) in children and adolescents. However, it was unclear in adults. We aimed to investigate the features of pituitary–TH actions in women and men at different ages, and the associations of thyrotropin (TSH), THs, and central sensitivity to THs indices including the thyroid feedback quantile-based index by FT4 (TFQIFT4) and the thyroid feedback quantile-based index by FT3(TFQIFT3) with of TNs in Chinese euthyroid adults.Methods8771 euthyroid adults from the communities in China were involved. Demographic, behavioral, and anthropometric data were gathered through the questionnaires. Ultrasound was performed to evaluate the TNs. TSH and THs levels were measured. The multivariable logistic regression and multivariable ordinal logistic regression were conducted.ResultsTFQIFT3 among both genders, except women aged 43 to 59 years, where it increased slightly. Additionally, there was an age-related decline in TFQIFT4 levels in both women and men at ages < 50 and < 53, respectively, but a marked increase after that. Lower TSH levels were significantly associated with a higher prevalence and lower odds of having fewer TNs using multiple nodules as the base category in both men and women (both P for trend < 0.05). Additionally, lower TFQIFT3 and TFQIFT4 levels were significantly associated with a higher prevalence of TNs in women (both P for trend < 0.05), and lower TFQIFT3 levels were significantly associated with a higher prevalence of TNs in men. Both higher TFQIFT3 and TFQIFT4 levels were significantly associated with higher odds of having fewer TNs using multiple nodules as the base category in women. However, the relationships between TFQIFT4 and the prevalence or number of TNs in men were not found.ConclusionsThe trends of THs, TSH, TFQIFT4, and TFQIFT3 at different ages were sex-dependent. Both TFQIFT4 and TFQIFT3 levels were negatively associated with the prevalence and number of TNs in women. The present results may lead to a better understanding of the sex-specific relationships between the development of the pituitary-TH axis and the formation of TNs.

Rosai–Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by massive lymphadenopathy and systemic extranodal lesions. We present the case of a 28-year-old woman who presented with recurrent blurred vision in her right eye for 3 months. She developed blindness and atrophy in her left eye a decade prior to presentation. She subsequently developed headache, fever, and impaired mental status. Cranial magnetic resonance imaging indicated hypertrophic pachymeningitis (HP), and 18 F-fluoro-2-deoxy-2- d -glucose (FDG) positron emission tomography/computed tomography revealed significant FDG uptake in the left dura mater. Autoimmune testing revealed elevated anti-nuclear, anti-SS-A, and anti-SS-B antibody levels. Incisional biopsy of the atrophic eyeball revealed RDD with marked polyclonal plasmacytosis. The patient was diagnosed with RDD accompanied by multisystem involvement, including Sjögren’s syndrome (SS), panuveitis, and HP. Treatment with methylprednisolone for several weeks resulted in significant improvement. This is the first reported case of RDD presenting with SS in combination with panuveitis and HP. Although RDD is rarely diagnosed in young patients, interdisciplinary collaboration is essential to prevent a delayed diagnosis.

Objective: To investigate the utility of texture data based on T2-weighted magnetic resonance imaging (MRI) in determining intervertebral disc degeneration in adolescent idiopathic scoliosis (AIS). Materials and Methods：From October 2016 and March 2020, 122 patients with AIS and 40 volunteers who underwent 3.0T MRI were prospectively included. The following MRI texture data were generated: (1) mean, (2) standard deviation, (3) max, (4) min, (5) the fifth, 10th, 25th, 50th, 75th and 90th percentiles; (6) skewness; (7) kurtosis; and (8) entropy. The Pfirrmann system was used to evaluate the intervertebral discs of all participants. Patients with Pm I were divided into groups 1 and 2. Volunteers were classified into 0. Differences and correlations between the groups were analyzed. Results: The mean, standard deviation, max, entropy and the 5th, 10th, 25th, 50th, 75th, and 90th percentiles in group 2 were significantly lower than those in group 1 and group 0; the min in group 2 was significantly lower than in group 0; the skewness in group 2 was significantly higher than in group 1 and group 0; the kurtosis in group 2 was significantly lower than in group 1; the skewness in group 1 was significantly higher than in group 0 and the standard deviation, min, kurtosis and 5th, 10th, 25th, and 50th percentiles in group 1 were significantly lower than those in group 0. Conclusion: Texture analysis can be used to assess early degenerative changes in the intervertebral discs of patients with AIS.

Abstract CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

Eriobotrya japonica (E. japonica) leaves have been used as an herbal traditional medicine in China and Japan owing to their anti-inflammatory and protective effects against skin conditions and allergy symptoms. These beneficial effects are likely mediated by the various triterpenoids present in E. japonica leaves. However, the efficacy of E. japonica leaves in the treatment of allergic rhinitis has not been evaluated in humans. Therefore, in the present study, a randomized, controlled, double-blind trial was performed on healthy adults of age >20 (n = 27) who were randomly assigned to receive either 2.5 g of placebo or E. japonica leaf supplements once daily for 4 weeks. The Japanese Allergic Rhinitis Quality of Life Standard Questionnaire (JRQLQ), dermatological allergy symptoms, Dermatology Life Quality Index, and skin condition parameters were assessed at baseline and after 4 weeks. Significant differences were observed in the variability of the itchy nose, itchy eyes, and eye symptoms between the E. japonica supplementation and placebo groups after 4 weeks. Arm skin transepidermal water loss was improved only in the E. japonica supplementation group. This study suggests that E. japonica leaves can be used as a functional food ingredient to relieve allergic symptoms.

Abstract Background Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis. Methods Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography–tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism. Results Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948. Conclusion In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2.

ABSTRACT: Objectives: The aim of the study was to update the classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens. Group A drugs (fluoroquinolones, bedaquiline (BDQ), and linezolid (LZD)) are crucial drugs for the control of MDR-TB. Molecular drug resistance assays could facilitate the effective use of Group A drugs. Methods: We summarised the evidence implicating specific genetic mutations in resistance to Group A drugs. We searched PubMed, Embase, MEDLINE, and the Cochrane Library for studies published from the inception of each database until July 1, 2022. Using a random-effects model, we calculated the odds ratios and 95% confidence intervals as our measures of association. Results: A total of 5001 clinical isolates were included in 47 studies. Mutations in gyrA A90V, D94G, D94N, and D94Y were significantly associated with an increased risk of a levofloxacin (LFX)-resistant phenotype. In addition, mutations in gyrA G88C, A90V, D94G, D94H, D94N, and D94Y were significantly associated with an increased risk of a moxifloxacin (MFX)-resistant phenotype. In only one study, the majority of gene loci (n = 126, 90.65%) in BDQ-resistant isolates were observed to have unique mutations in atpE, Rv0678, mmpL5, pepQ, and Rv1979c. The most common mutations occurred at four sites in the rrl gene (g2061t, g2270c, g2270t, and g2814t) and at one site in rplC (C154R) in LZD-resistant isolates. Our meta-analysis demonstrated that there were no mutations associated with BDQ- or LZD-resistant phenotypes. Conclusion: The mutations detected by rapid molecular assay were correlated with phenotypic resistance to LFX and MFX. The absence of mutation-phenotype associations for BDQ and LZD hindered the development of a rapid molecular assay.

Purpose: Treatment of triple-negative breast cancer (TNBC) remains challenging. Intermittent fasting (IF) has emerged as a promising approach to improve metabolic health of various metabolic disorders. Clinical studies indicate IF is essential for TNBC progression. However, the molecular mechanisms underlying metabolic remodeling in regulating IF and TNBC progression are still unclear. Methods: In this study, we utilized a robust mouse model of TNBC and exposed subjects to a high-fat diet (HFD) with IF to explore its impact on the metabolic reprogramming linked to cancer progression. To identify crucial serum metabolites and signaling events, we utilized targeted metabolomics and RNA sequencing (RNA-seq). Furthermore, we conducted immunoblotting, real-time quantitative polymerase chain reaction (RT-qPCR), cell migration assays, lentivirus-mediated Mmp9 overexpression, and Mmp9 inhibitor experiments to elucidate the role of decanoylcarnitine/Mmp9 in TNBC cell migration. Results: Our observations indicate that IF exerts notable inhibitory effects on both the proliferation and cancer metastasis. Utilizing targeted metabolomics and RNA-seq, we initially identified pivotal serum metabolites and signaling events in the progression of TNBC. Among the 349 serum metabolites identified, decanoylcarnitine was picked out to inhibit TNBC cell proliferation and migration. RNA-seq analysis of TNBC cells treated with decanoylcarnitine revealed its suppressive effects on extracellular matrix-related protein components, with a notable reduction observed in Mmp9. Further investigations confirmed that decanoylcarnitine could inhibit Mmp9 expression in TNBC cells, primary tumors, lung, and liver metastasis tissues. Mmp9 overexpression abolished the inhibitory effect of decanoylcarnitine on cell migration. Conclusion: This study pioneers the exploration of IF intervention and the role of decanoylcarnitine/Mmp9 in the progression of TNBC in obese mice, enhancing our comprehension of the potential roles of various dietary patterns in the process of cancer treatment.

Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.

BackgroundInterpersonal violence (IPV) against young women, including physical and sexual violence, poses a major threat to public health. We analyzed global, regional and national trends in violence against females aged 10–24 years from 1990 to 2019.MethodsWe extracted age-standardized prevalence rates (ASPRs) of physical violence by firearm (PVF), physical violence by other means (PVOM), physical violence by sharp object (PVSO), and sexual violence (SV) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Joinpoint regression analysis calculated annual and average annual percentage changes (AAPCs) in ASPRs.ResultsGlobally, the ASPRs of the four measures of IPV decreased between 1990 and 2019, with the steepest declines between 2000 and 2009, except for SV, which increased slightly. However, the ASPRs of PVF and PVOM increased slightly between 2010 and 2019. Regionally, PVF prevalence declined most in East Asia (−0.9505, −1.0011 to −0.8975), South Asia (−0.277, −0.3089 to −0.244) and Latin America but PVOM prevalence increased in Oceania (0.6275, 0.6036 to 0.6498) and SV prevalence increased in Caribbean (0.4267, 0.4069 to 0.4495). Nationally, PVF prevalence decreased most in Thailand (−2.4031, −2.4634 to −2.3328) but increased most in Libya (6.8143, 6.6194 to 7.0113). SV prevalence increased most in Oman (0.4561, 0.4338 to 0.478) and the largest increase in Disability-adjusted life years (DALYs) from PVOM was observed in Botswana (6.2725, 6.0951 to 6.4082). DALYs showed similar trends.ConclusionWhile global declines over 30 years are encouraging, IPV against young women persists. Urgent, tailored approaches across sectors are critical to curb drivers of violence against young women, including poverty, inequality and sociocultural attitudes. High-quality data and in-depth analyses can inform locally-relevant solutions. Overall, intensified political will and resource investment are needed to overcome this pervasive human rights violation.

Background: Generalized convulsive status epilepticus (GCSE) is one of the most challenging life-threatening neurological emergencies. If GCSE becomes super-refractory, it is associated with significant mortality. Although aggressive management of prolonged status epilepticus was conducted, the mortality has not decreased since the late 1990s. Objectives: The present study aimed to explore the risk factors for progression to super-refractory in patients with generalized convulsive status epilepticus (GCSE). Moreover, we illustrated the risk factors for mortality in GCSE patients. Design: An observational retrospective cohort study. Methods: We conducted a retrospective study of patients with GCSE admitted to our neurocritical unit, in Guangzhou, China, from October 2010 to February 2021. The data of sociodemographic information, etiology, laboratory results, treatment, and prognosis were collected and analyzed. Results: A total of 106 patients were enrolled; 51 (48%) of them developed super-refractory status epilepticus (SRSE). Multivariate logistic regression analysis demonstrated that patients with autoimmune encephalitis ( p = 0.015) and intracranial infection ( p = 0.019) are likely to progress to SRSE. The in-hospital mortality was 11.8% and 9.1% for patients in the SRSE and non-SRSE groups, respectively ( p = 0.652). Multivariate logistic regression analysis showed that neutrophil-to-lymphocyte ratios (NLR) at admission were independently associated with in-hospital mortality. Up to 31.4% of SRSE patients and 29.1% of non-SRSE patients died within 6 months after discharge ( p = 0.798). Multivariate logistic regression analysis showed that plasma exchange (PE) was a protective factor for 6-month mortality. A high NLR at discharge was a risk factor for 6-month mortality. Conclusion: In the current study, about 48% of GCSE patients progressed to SRSE. Regarding etiology, autoimmune encephalitis or intracranial infection was prone to SRSE. No significant differences were observed in the in-hospital and 6-month mortality between SRSE and non-SRSE groups. Multivariate logistic regression analysis showed that NLR at admission and discharge was an independent predictor of in-hospital and 6-month mortality, respectively. Moreover, PE significantly reduced the 6-month mortality.

Alzheimer’s disease (AD) is a major health challenge due to its high morbidity. This study aimed to investigate the potential effects of defatted walnut powder (DWP), which is the residue obtained after extracting oil from walnut kernels, on memory improvement. HPLC was used to establish the fingerprints of 14 batches of DWP extract (DWPE) obtained from various origins. Behavioral experiments and functional indicators were conducted to evaluate the efficacy of DWPE on AD. The results indicated that DWPE regulated the cholinergic system disorder in brain tissue. Additionally, DWPE reduced oxidative stress levels, neuroinflammation, and the damage of pyramidal cells in both the cortex and the hippocampal CA3 region. Subsequently, targeted amino acid metabolomics, gut microbiota sequencing and fecal microbiota transplantation confirmed that DWPE played a regulatory role in amino acid metabolism regulated by gut microbiota, effectively decreasing the levels of fat-soluble neurotoxic factor ammonia.

Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3–Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.

When the gas pipeline leaks, it causes huge economic losses. This paper establishes a digital twin model of a pipeline based on the pressure signal generated by a pipeline leak and researches on pipeline leak detection. First, an online updating of the twin model is established to update the data of the physical information space and the parameters of the twin model online. Second, a visual model is established to display the spatial data of physical information of pipelines and output data of the digital twin of pipelines in real-time. If pipeline leakage is identified, an alarm would be triggered and a corresponding emergency rescue plan would be initiated based on the the leakage. Finally, the pipeline leakage identification model can be established by analysing the finite element model of the pipeline, and the sample data were obtained and preprocessed to extract the feature vectors. The training model of the Support vector machine (SVM) was used to classify the working conditions. Theoretical analysis and experimental results show that the method proposed in this paper has high detection accuracy, so it is feasible to judge gas pipeline leakage by using digital twin prediction.

Abstract Background Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1). Methods Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined. Results Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3−, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6−Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase. Conclusions Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

Abstract Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.

Abstract Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality. MOF-regulated genes are highly enriched for essential functions in the mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for the electron transport chain (ETC) Complex III, in the skin, recapitulates the defects in epidermal differentiation and hair follicle growth observed in MOF knockout mouse. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for regulating mitochondrial and ciliary gene expression and underscores the important function of the MOF/ETC axis for mammalian skin development.

Abstract To determine the association between cell-free DNA fetal fraction (cffDNA) and various prenatal characters to better guide the clinical application of noninvasive prenatal screening (NIPS), a retrospective cohort study of 27,793 women with singleton pregnancies was conducted. Results indicated that no significant difference on cffDNA between trisomy/sex chromosome aneuploidy (SCA) and non-trisomy groups was found. However, the fetal fraction (FF) in the T18 and T13 subgroups were significantly lower than that in the non-trisomy group, while the FF in the T21 group was significantly higher than the non-trisomy group. Pearson’s correlation analysis revealed a positive correlation between √FF and gestational week in the T21, SCA, and non-trisomy groups. A negative correlation between maternal age and √FF in T21 and non-trisomy cases was found, but a positive correlation in SCA group. Compared to the decreasing trend in FF in the T21 group, no significant difference was observed in the SCA group. The √FF level was negatively correlated to maternal BMI in T21 and non-trisomy group, while a positive correlation in SCA group. FF was close related to the result of NIPS and related maternal factors. Though NIPS has increased accuracy, the complexity still should be recognized especially in clinical practice.

Abstract Background Glucose repression in yeast leads to the sequential or diauxic utilization of mixed sugars and reduces the co-utilization of glucose and xylose from lignocellulosic biomasses. Study of the glucose sensing pathway helps to construct glucose repression-released yeast strains and enhance the utilization of lignocellulosic biomasses. Results Herein, the glucose sensor/receptor repressor (SRR) pathway of Kluyveromyces marxianus which mainly consisted of KmSnf3, KmGrr1, KmMth1, and KmRgt1 was studied. The disruption of KmSNF3 led to a release of glucose repression, enhanced xylose consumption and did not result in deficient glucose utilization. Over-expression of glucose transporter gene restored the mild decrease of glucose utilization ability of Kmsnf3 strain to a similar level of the wildtype strain but did not restore glucose repression. Therefore, the repression on glucose transporter is parallel to glucose repression to xylose and other alternative carbon utilization. KmGRR1 disruption also released glucose repression and kept glucose utilization ability, although its xylose utilization ability was very weak with xylose as sole carbon source. The stable mutant of KmMth1-ΔT enabled the release of glucose repression irrespective that the genetic background was Kmsnf3, Kmmth1, or wildtype. Disruption of KmSNF1 in the Kmsnf3 strain or KmMTH1-ΔT overexpression in Kmsnf1 strain kept constitutive glucose repression, indicating that KmSNF1 was necessary to release the glucose repression in both SRR and Mig1-Hxk2 pathway. Finally, overexpression of KmMTH1-ΔT released the glucose repression to xylose utilization in S. cerevisiae. Conclusion The glucose repression-released K. marxianus strains constructed via a modified glucose SRR pathway did not lead to a deficiency in the utilization ability of sugar. The obtained thermotolerant, glucose repression-released, and xylose utilization-enhanced strains are good platforms for the construction of efficient lignocellulosic biomass utilization yeast strains.

Abstract Colon cancer is a common malignancy of the digestive tract. Colon cancer stem-like cells (CCSCs) are theoretically one of the key drivers of the initiation, relapse, metastasis, and chemo-resistance of colon tumors. Piezo1 is a mechanosensitive cationic channel protein involved in cancer progression. However, little is known regarding the possible role of Piezo1 in maintaining the stemness of CCSCs. In this study, we found that Piezo1 was highly expressed in CD133+/CD44+ colon cancer tissues, and the Piezo1high/CD133+CD44+ population was associated with the clinical stage. Furthermore, CCSCs isolated from colon cell lines expressed higher Piezo1 levels compared to the non-CCSCs, and Piezo1 knockdown inhibited their tumorigenicity and self-renewal capacity. Mechanistically, Piezo1 maintained the stemness of CCSCs through Ca2+/NFAT1 signaling, and knocking down Piezo1 promoted degradation of NFAT1. Taken together, Piezo1 is involved in the stage of colon cancer and is a promising therapeutic target.

Numerous studies have shown that the endophytic fungus Piriformospora indica has a broad range of promoting effects on root development and plant growth in host plants. However, there are currently no reports on the application of this fungus on Cerasus humilis. This study first compared the colonization ability of P. indica on 11 C. humilis varieties and found that the colonization rate of this fungus on these varieties ranged from 90% to 100%, with the colonization rate of the varieties ‘09-01’ and ‘Nongda 7’ being as high as 100%. Subsequently, the effect of P. indica on root development and plant growth of C. humilis was investigated using cuttings of ‘09-01’ and ‘Nongda 7’ as materials. P. indica colonization was found to increase the biomass of ‘09-01’ and ‘Nongda 7’ plants; root activity, POD enzymes, and chlorophyll content were also significantly increased. In addition, indole-3-acetic acid (IAA) content in the roots of C. humilis plants increased after colonization, while jasmonic acid (JA) and 1-aminocyclopropane-1-car- boxylic acid (ACC) content decreased. In conclusion, it has been demonstrated that P. indica can promote the growth of C. humilis plants by accelerating biomass accumulation, promoting rooting, and enhancing the production of photosynthetic pigments, as well as regulating hormone synthesis.

Asarum is a traditional Chinese medicinal plant, and its dried roots are commonly used as medicinal materials. Research into the traits of the bacteria and fungus in the Asarum rhizosphere and how they relate to the potency of medicinal plants is important. During four cropping years and collecting months, we used ITS rRNA gene amplicon and sequencing to assess the population, diversity, and predominant kinds of bacteria and fungus in the rhizosphere of Asarum. HPLC was used to determine the three bioactive ingredients, namely asarinin, aristolochic acid I, and volatile oil. The mainly secondary metabolites of Asarum, relationships between microbial communities, soil physicochemical parameters, and possible influences on microbial communities owing to various cropping years and collecting months were all statistically examined. The cropping years and collecting months affected the abundance and diversity of rhizosphere bacteria and fungi, but the cropping year had a significant impact on the structures and compositions of the bacterial communities. The rhizosphere microorganisms were influenced by both the soil physicochemical properties and enzyme activities. Additionally, this study revealed that Trichoderma was positively correlated with the three bioactive ingredients of Asarum, while Tausonia showed entirely opposite results. Gibberella and Leptosphaeria demonstrated a significantly negative correlation with asarinin and violate oil, but they were weakly correlated with the aristolochic acid I content. This study revealed variations in the Asarum rhizosphere microorganism population, diversity, and dominant types across four cropping years and collecting months. The relationship between Asarum secondary metabolites, the soil physicochemical properties, enzyme activities, and rhizosphere microorganisms was discussed. Our results will guide the exploration of the soil characteristics and rhizosphere microorganisms’ structures by regulating the microbial community to enhance Asarum quality.

Abstract Diffuse large B-cell lymphoma (DLBCL) is malignant hyperplasia of B lymphocytes and standard care cannot satisfactorily meet clinical needs. Potential diagnostic and prognostic DLBCL biomarkers are needed. NCBP1 could bind to the 5ʹ-end cap of pre-mRNAs to participate in RNA processing, transcript nuclear export and translation. Aberrant NCBP1 expression is involved in the pathogenesis of cancers, but little is known about NCBP1 in DLBCL. We proved that NCBP1 is significantly elevated in DLBCL patients and is associated with their poor prognosis. Then, we found that NCBP1 is important for the proliferation of DLBCL cells. Moreover, we verified that NCBP1 enhances the proliferation of DLBCL cells in a METTL3-dependent manner and found that NCBP1 enhances the m6A catalytic function of METTL3 by maintaining METTL3 mRNA stabilization. Mechanistically, the expression of c-MYC is regulated by NCBP1-enhanced METTL3, and the NCBP1/METTL3/m6A/c-MYC axis is important for DLBCL progression. We identified a new pathway for DLBCL progression and suggest innovative ideas for molecular targeted therapy of DLBCL.

Abstract Background Venetoclax (Ven) combined with intensive chemotherapy was proven effective in the management of acute myeloid leukemia (AML). However, the severe and prolonged myelosuppression remains a concern to worry about. To explore more appropriate combination regimens, we designed Ven combining daunorubicin and cytarabine (DA 2 + 6) regimen as induction therapy, aimed to evaluate the effectiveness and safety in adults de novo AML. Methods A phase 2 clinical trial was performed in 10 Chinese hospitals to investigate Ven combined with daunorubicin and cytarabine (DA 2 + 6) in patients with AML. The primary endpoints were overall response rate (ORR), comprising of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints included measurable residual disease (MRD) of bone marrow assessed by flow cytometry, overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. This study is a currently ongoing trial listed on the Chinese Clinical Trial Registry as ChiCTR2200061524. Results Overall, 42 patients were enrolled from January 2022 to November 2022; 54.8% (23/42) were male, and the median age was 40 (range, 16–60) years. The ORR after one cycle of induction was 92.9% (95% confidence interval [CI], 91.6–94.1; 39/42) with a composite complete response rate (CR + CRi) 90.5% (95% CI, 89.3–91.6, CR 37/42, CRi 1/42). Moreover, 87.9% (29/33) of the CR patients with undetectable MRD (95% CI, 84.9–90.8). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (90.5%), and one mortality. The median neutrophil and platelet recovery times were 13 (5–26) and 12 (8–26) days, respectively. Until Jan 30, 2023, the estimated 12-month OS, EFS, and DFS rates were 83.1% (95% CI, 78.8–87.4), 82.7% (95% CI, 79.4–86.1), and 92.0% (95% CI, 89.8–94.3), respectively. Conclusion Ven with DA (2 + 6) is a highly effective and safe induction therapy for adults with newly diagnosed AML. To the best of our knowledge, this induction therapy has the shortest myelosuppressive period but has similar efficacy to previous studies.

Abstract Background Geranylgeranyl pyrophosphate synthase (GGPS) is a structural enzyme of the terpene biosynthesis pathway that is involved in regulating plant photosynthesis, growth and development, but this gene family has not been systematically studied in cotton. Results In the current research, genome-wide identification was performed, and a total of 75 GGPS family members were found in four cotton species, Gossypium hirsutum, Gossypium barbadense, Gossypium arboreum and Gossypium raimondii. The GGPS genes were divided into three subgroups by evolutionary analysis. Subcellular localization prediction showed that they were mainly located in chloroplasts and plastids. The closely related GGPS contains a similar gene structure and conserved motif, but some genes are quite different, resulting in functional differentiation. Chromosome location analysis, collinearity and selection pressure analysis showed that many fragment duplication events occurred in GGPS genes. Three-dimensional structure analysis and conservative sequence analysis showed that the members of the GGPS family contained a large number of α-helices and random crimps, and all contained two aspartic acid-rich domains, DDxxxxD and DDxxD (x is an arbitrary amino acid), suggesting its key role in function. Cis-regulatory element analysis showed that cotton GGPS may be involved in light response, abiotic stress and other processes. A GGPS gene was silenced successfully by virus-induced gene silencing (VIGS), and it was found that the chlorophyll content in cotton leaves decreased significantly, suggesting that the gene plays an important role in plant photosynthesis. Conclusions In total, 75 genes were identified in four Gossypium species by a series of bioinformatics analysis. Gene silencing from GGPS members of G. hirsutum revealed that GGPS plays an important regulatory role in photosynthesis. This study provides a theoretical basis for the biological function of GGPS in cotton growth and development.

Abstract It is very important to consider the eddy current reaction of the metal structure in large electric machines, which has a direct impact on the calculation results of induced current and loss. In order to solve the problem that the complex end leakage magnetic field is difficult to calculate directly, a new semi‐analytical method (NSM) considering the eddy current reaction is proposed. Firstly, the corresponding relationship between the external magnetic field and the global magnetic field of the clamping ring in two simple calculation models is obtained by the 3‐D finite element method. Then, the external magnetic field of the clamping ring in a 300MVA synchronous condenser under rated operating conditions is calculated, and the global magnetic field of the clamping ring is determined based on the obtained corresponding relationship. The eddy current density and eddy current loss of the clamping ring are calculated using the external magnetic field and the global magnetic field respectively. Finally, the calculation results were compared with the 3‐D finite element results, which verified the importance of the global magnetic field and the accuracy of the NSM.

This study aims to discuss the impact of teacher care behavior on EFL learning anxiety, as well as the mediating role of learning engagement and learning strategies. The Process plugin Model6 was used to measure the interaction between teacher care behavior (TCB), EFL learning anxiety (EFLLA), learning engagement (LE), and English learning strategies (ELS), in order to analyze and summarize their impact characteristics on college students’ EFL learning anxiety. The results show that teacher care behavior has a direct impact on EFL learning anxiety and a significant negative predictive effect on it. Learning engagement and English learning strategies play a mediating and chain mediating role between teacher care behavior and EFL learning anxiety. Thus, it can be seen that these factors can help reduce EFL learning anxiety, manifested in aspects such as mood, cognition, emotion, and behavior. Given the research findings, this study further provides suggestions for alleviating college students’ EFL learning anxiety, optimizing English teaching and learning design, and cultivating English learning strategies for college students.

Background: Traumatic events can cause social tension, anxiety, panic and other psychological crises, and can even cause post-traumatic stress disorder (PTSD) and suicide. Physical activity has a good role in promoting mental health, and has a great application prospect in individual psychological intervention after traumatic events. However, no systematic review of the relationship between physical activity and individual mental health after traumatic events affecting many people has been published so far, which makes it impossible for people to understand the research status in this field from a holistic perspective. Objective: This review explores the relationship between physical activity and individual psychology, physiology, subjective quality of life and well-being after traumatic events, so as to provide some valuable clues or enlightenment for individual psychological intervention after traumatic events. Method: Relevant literature was searched in five databases, summarised, sorted and studied. Results: Thirty-three study papers were included in this review, the main study findings include: (1) Physical activity is positively correlated with individual mental resilience and subjective well-being after traumatic events, and negatively correlated with anxiety, depression, tension and PTSD. (2) Individuals with higher levels of physical activity have better mental health status after traumatic events than those who do not regularly engage in physical activity. (3) Physical activity can promote sleep quality, self-efficacy, subjective quality of life and various physiological functions of those experiencing traumatic events. (4) Physical activity (including exercise) is regarded as one of the preferred nursing measures to buffer against mental stress and maintain physical and mental health for those experiencing traumatic events. Conclusion: The level of physical activity is positively correlated with individual physical and mental health before and after traumatic events. Physical activity can be used as one of the effective measures to improve individual mental health after traumatic events.