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Abstract Background Due to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD. Methods We established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with PAH-CHD was measured by ELISA. Results THBS4 was upregulated in the lung tissues of MCT-AV rats, and was further upregulated in severe pulmonary vascular lesions. And THBS4 was expressed mainly in PASMCs. When THBS4 was inhibited, contractile markers α-SMA and MYH11 were upregulated, while the proliferative marker PCNA was decreased, the endothelial-mensenchymal transition marker N-cad was downregulated, proapototic marker BAX was increased. Additionally, proliferation and migration of PASMCs was inhibited and apoptosis was increased. Conversely, THBS4 overexpression resulted in opposite effects. And the impact of THBS4 on PASMCs was probably achieved through the regulation of the PI3K/AKT pathway. THBS4 suppression attenuated pulmonary vascular remodeling. Furthermore, compared with patients with simple congenital heart disease and mild PAH-CHD, the circulating level of THBS4 was higher in patients with severe PAH-CHD. Conclusions THBS4 is a promising biomarker to distinguish reversible from irreversible PAH-CHD before repairing the shunt. THBS4 is a potential treatment target in PAH-CHD, especially in irreversible stage.

Abstract Background and aims The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. Methods The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. Results Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). Conclusion Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

Abstract Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b, loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged.

Background Personal and family history of psychiatric disorders are key risk factors for postpartum depression (PPD), yet their combined contribution has been understudied.Objective To examine personal and family psychiatric history, alone and combined, and their effect on absolute risk and relative risk (RR) of mild/moderate or severe PPD.Methods In this cohort study, we used data from 142 064 childbirths with PPD screenings from 2015 to 2021 merged with population registers. Exposures were personal and family psychiatric history defined as a psychiatric hospital contact or psychotropic prescription fills by index mothers and their parents prior to delivery. Outcomes were mild/moderate PPD (Edinburgh Postnatal Depression Scale, cut-off: ≥11 within 12 weeks post partum) and severe PPD (antidepressant fill or depression diagnosis within 6 months post partum). We calculated absolute risks and RRs using Poisson regression models adjusted for parity, education, maternal age, and calendar year.Findings Of the 142 064 participants, 23.4% had no psychiatric history, 47.4% had only family history, 6.0% had only personal history, and 23.2% had both. The latter group had the highest risk of PPD: absolute risk of mild/moderate PPD was 11.7% (95% CI 11.5%; 11.8%), and adjusted RR: 2.35 (95% CI 2.22; 2.49). Alone, personal psychiatric history was the most potent risk factor. Dose–response relationship based on severity of personal and family psychiatric history was found.Discussion Our study documents a substantial association between personal and family psychiatric history and PPD risk.Clinical implications Evaluating combinations of risk factors is important to improve risk assessment.

Abstract Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease. Identifying biomarkers for early diagnosis is of great clinical importance. The epididymis protein 4 (HE4) is important in the process of inflammation and fibrosis in the epididymis. Its prognostic value in IPF, however, has not been studied. The mRNA and protein levels of HE4 were used to determine the prognostic value in different patient cohorts. In this study, prognostic nomograms were generated based on the results of the cox regression analysis. We identified the HE4 protein level increased in IPF patients, but not the HE4 gene expression. The increased expression of HE4 correlated positively with a poor prognosis for patients with IPF. The HR and 95% CI were 2.62 (1.61–4.24) (p

Abstract Background Genome-scale screening can be applied to efficiently mine for unknown genes with phenotypes of interest or special functions. It is also useful to identify new targets for engineering desirable properties of cell factories. Results Here, we designed a new approach for genome-scale transcription activation using non-homologous end joining (NHEJ)-mediated integration in Yarrowia lipolytica. We utilized this approach to screen for genes that, upon activation, confer phenotypes including improved acetic acid tolerance and xylose metabolism. The candidates were validated using gene overexpression, and functional changes including improved growth performance under multiple stressors and activated pentose metabolism were identified. Conclusions This study provides a simple and effective approach to randomly activate endogenous genes and mine for key targets associated with phenotypes of interest. The specific gene targets identified here will be useful for cell factory construction and biorefining lignocellulose.

Abstract Light undergoes attenuation due to scattering and refraction when propagating through aerosols. In foggy conditions, Aerosol particles in the troposphere exhibit high mobility introducing intricate non‐linear noise into images. Foggy image restoration represents an ill‐posed problem, where traditional physical models and image enhancement techniques often prove inadequate in delivering effective solutions. This paper introduces a novel deep sub‐pixel reconstruction algorithm for foggy image restoration, pioneering the application of sub‐pixel reconstruction modules to this domain. This model employs convolutional layers to extract low‐level features and dense‐connected layers for high‐level feature extraction. Furthermore, a specialized sub‐pixel reconstruction module tailored for the task of foggy image restoration is designed, with the purpose of reconstructing dehazed images from latent vectors. During training, a generative adversarial training framework is adopted, incorporating a purpose‐designed discriminator. Additionally, a fusion loss is implemented to facilitate model refinement. Quantitative and qualitative evaluation experiments conducted on synthetic and real‐world image datasets demonstrate the effectiveness of the proposed method in preserving finer details. The Structural Similarity Index (SSIM) is observed to improve by 2.5%, attesting to enhanced perceptual quality for grayscale foggy images.

Introduction This study combined the bioinformatics and in vitro experiment-related technologies to analyze the impact of steroid 5 alpha-reductase 3 (SRD5A3) on the prognosis and immune microenvironment of Liver Hepatocellular Carcinoma (LIHC).Method Gene expression and clinical data were obtained from public databases. The prognosis was evaluated using survival, multifactor Cox, enrichment, and mutation analyses. This was then verified through in vitro experiments.Results The expression level of SRD5A3 in LIHC tissues was significantly higher than that in the adjacent tissues. Kaplan–Meier survival analysis showed that high SRD5A3 expression was associated with poor overall survival (OS) and short progression-free survival in patients with LIHC. Multivariate Cox regression analysis revealed that positive SRD5A3 expression was an independent risk factor for OS in patients with LIHC. Expression of SRD5A3 was negatively correlated with immune cell infiltration of CD4+ T, CD8+ T, and B cells. GO and KEGG enrichment analyses showed that SRD5A3 was significantly enriched in signaling- and tumor metastasis-related pathways. Nomogram and calibration curve showed that the predicted performance of the model was consistent with the actual results. In vitro results confirmed that SRD5A3 knockdown inhibited the migration, invasion, and proliferation of LIHC cells.Conclusions SRD5A3 is actively expressed in LIHC, and positive expression of SRD5A3 is an independent risk factor for different prognoses in patients with LIHC. SRD5A3 can promote the proliferation, migration, and invasion of liver cancer cells and is related to short immune infiltration in patients with LIHC.

AbstractBackground Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors.Methods Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed.Results A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI= (1.011, 1.142)] was an independent predictor of IPF combined with anxiety (p

Fibrosis is a public health issue of great concern characterized by the excessive deposition of extracellular matrix, leading to the destruction of parenchymal tissue and organ dysfunction that places a heavy burden on the global healthcare system due to its high incidence, disability, and mortality. Salvianolic acid B (SalB) has positively affected various human diseases, including fibrosis. In this review, we concentrate on the anti-fibrotic effects of SalB from a molecular perspective while providing information on the safety, adverse effects, and drug interactions of SalB. Additionally, we discuss the innovative SalB formulations, which give some references for further investigation and therapeutic use of SalB’s anti-fibrotic qualities. Even with the encouraging preclinical data, additional research is required before relevant clinical trials can be conducted. Therefore, we conclude with recommendations for future studies. It is hoped that this review will provide comprehensive new perspectives on future research and product development related to SalB treatment of fibrosis and promote the efficient development of this field.

Rhamnus utilis Decne. (Family Rhamnaceae Juss.) leaf is commonly prepared as a anti-inflammatory herbal medicine and used for tea production. To investigate the mechanism of Rhamnus utilis Decne. aqueous extract (RDAE) against acute alcoholic liver disease (ALD) in mice. The ALD mouse (Male ICR) model was induced via intragastric administration of 52 % alcohol. Mice in each group were treated by gavage once daily with the RDAE (1.12, 2.25, 4.500 g/kg). The expression of proteins involved in the MAPKs/NF-κB/COX-2-iNOS pathway was measured by western blotting. Non-targeted metabolomics was used to determine metabolic profiles and critical pathways, while targeted metabolomics validated key amino acid metabolites. After administration of RDAE, the body mass of mice was significantly increased. The liver index was significantly decreased. Meanwhile, the serum levels of AST, ALT, TG, TC, MDA, TNF-α, IL-1β and IL-6 were significantly decreased (P

Members of bZIP gene family play crucial roles in various biological processes, including plant growth and development, stress response, and light signal transduction. Despite their significance, there is limited information on the function of the bZIP gene family in peanuts. In this investigation, we identified a total of 99 bZIP gene family members in the peanut genome, distributed across 20 chromosomes. Phylogenetic tree analysis categorized the peanut bZIP gene family into 10 groups, with groups I, D, A and S being the most widely distributed. Transcriptome analysis of peanut pods revealed that 10 bZIP family genes exhibited significant induction in response to light, suggesting their potential involvement in light signal transduction in peanuts. Within the peanut bZIP family, group H comprises six genes AhbZIP13, AhbZIP63, AhbZIP39, AhbZIP44, AhbZIP91 and AhbZIP96. Particularly, the expression of the AhbZIP63 (AhHYH) gene significantly increased under light induction, indicating a pivotal role in light signal transduction. DAP-seq analysis of AhbZIP63 (AhHYH) demonstrated its direct regulation of genes associated with UV response and cellular response to nutrient levels.

Abstract In the face of the problem of waste disposal in the demolition of concrete structures, a composite wall composed of recycled concrete bricks and fly ash blocks was proposed, and based on the previous thermal performance research, its axial compression performance were further studied. Four types of walls were designed and constructed: (1) clay brick masonry (CBM), (2) recycled concrete brick masonry (RBM), (3) bilateral clay bricks masonry with coal-ash blocks sandwich insulation wall (CFCM), and (4) bilateral recycled concrete bricks masonry with coal-ash blocks sandwich insulation wall (RFRM). The test results showed that recycled concrete brick masonry exhibited a higher bearing capacity than clay brick masonry. The ultimate load of RBM was 15% higher than that of CBM. Moreover, the ultimate load of CFCM was 21% higher than that of CBM. Following the addition of sandwich coal-ash blocks in RBM, its ultimate load increased by over 42% than that of CBM. Following the addition of coal-ash blocks sandwich in both clay and recycled concrete bricks masonry, both the bearing capacity and strain exhibited improvement, the yielding load and compressive strength of them increased. Thus, it could be concluded that coal-ash blocks improved its bearing capacity. Based on the analysis of the axial compression tests, a theoretical computational model was developed and a computational expression to explain the compressive bearing capacity of a two-sided brick with coal-ash blocks sandwich insulation wall. Comparisons between the test ultimate loads (FT) and the estimated ultimate loads (FE) confirmed the accuracy of the theoretical calculation model for the compressive bearing capacity. Thus, theoretical computational models are highly recommended for the design of two-sided bricks with insulating walls constructed from coal-ash blocks being sandwiched together. This study provides a theoretical basis for the engineering application of recycled concrete brick wall and fly ash block composite wall.

Abstract Background Existing research has established the pepsinogen ratio (PGR) as a complex biomarker, not only as an independent predictor for various gastrointestinal diseases but also in its association with atherosclerotic cardiovascular diseases. However, the precise mechanism linking changes in PGR to cardiovascular pathologies remains unclear. The objective of this study is to quantitatively elucidate the association between PGR and brachial-ankle pulse wave velocity (baPWV) as an indicator of atherosclerotic progression. Methods We conducted a cross-sectional study that analyzed clinical data from 465 patients who underwent health screenings. One-way Analysis of Variance (ANOVA) identified potential risk factors affecting baPWV. Multiple logistic regression was employed to evaluate if PGR serves as an independent risk factor for elevated baPWV after accounting for these variables. Generalized additive models and smoothed curve fitting were utilized to investigate the possibility of a nonlinear association between PGR and baPWV. When such nonlinearity was found, threshold effect analysis pinpointed the inflection point in this relationship, followed by segmented correlation analyses. Results PGR negatively correlated with both right baPWV (RbaPWV) and left baPWV (LbaPWV) after adjusting for confounders. Smoothed curve analyses revealed nonlinear relationships, with inflection points at 22.5 for RbaPWV and 22.3 for LbaPWV. For PGR values below 22.5, a significant negative correlation with RbaPWV was observed (β = − 6.3 cm/s, P

Abstract It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97–1.29) and 1.11 (0.97–1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account.

Micafungin (MFG) is a widely used echinocandin antifungal agent for treating invasive candidiasis, particularly in critically ill patients. However, its pharmacokinetics can be highly variable in this population. This systematic review aims to summarize population pharmacokinetic models and provide recommendations for its use in intensive care unit (ICU) patients. Monte Carlo simulations were implemented to compare pharmacokinetic parameters and probability of target attainment (PTA) against various Candida species. A total of 16 studies were included, of which 6 studies were conducted in adult ICU patients. The key covariates were body size, liver function, and sepsis-related organ failure assessment score (SOFA) score. The median MFG clearance in adult ICU patients was 30–51% higher than in adult non-ICU patients. For infections with C. albican with MIC below 0.016 mg/L, micafungin dosages of 100 and 150 mg/d were recommended for adult non-ICU and ICU patients, respectively. For C. tropicalis and C. glabrata, 200 and 250 mg/d were recommended, respectively. However, for C. krusei and C. parapsilosis, none of the tested dosage regimens achieved assumed PTA criteria within MIC ranges of 0.125–0.25 mg/L and 0.125–2 mg/L, respectively. Therefore, MFG dosage regimens in ICU and non-ICU patients should be tailored based on the Candida spp. and their respective MIC values.

Abstract Background Auxin is an important hormone in plants and the PIN-FORMED (PIN) genes are essential to auxin distribution in growth and developmental processes of plants. Peanut is an influential cash crop, but research into PIN genes in peanuts remains limited. Results In this study, 16 PIN genes were identified in the genome of cultivated peanut, resolving into four subfamilies. All PIN genes were predicted to be located in the plasma membrane and a subcellular location experiment confirmed this prediction for eight of them. The gene structure, cis-elements in the promoter, and evolutionary relationships were elucidated, facilitating our understanding of peanut PINs and their evolution. In addition, the expression patterns of these PINs in various tissues were analyzed according to a previously published transcriptome dataset and qRT-PCR, which gave us a clear understanding of the temporal and spatial expression of PIN genes in different growth stages and different tissues. The expression trend of homologous genes was similar. AhPIN2A and AhPIN2B exhibited predominant expression in roots. AhPIN1A-1 and AhPIN1B-1 displayed significant upregulation following peg penetration, suggesting a potential close association with peanut pod development. Furthermore, we presented the gene network and gene ontology enrichment of these PINs. Notably, AhABCB19 exhibited a co-expression relationship with AhPIN1A and AhPIN1B-1, with all three genes displaying higher expression levels in peanut pegs and pods. These findings reinforce their potential role in peanut pod development. Conclusions This study details a comprehensive analysis of PIN genes in cultivated peanuts and lays the foundation for subsequent studies of peanut gene function and phenotype.

Extruded corn flour can be easily agglomerated and poses poor flavor. Previous studies have found that phosphorylation heat treatment, enzyme treatment, edible gum dry heat treatment, and composite treatment could significantly reduce the agglomeration rate. The present study sought to explore the effects of sodium orthophosphate heat treatment (S1), neutral protease (S2), xanthan gum dry heat treatment (S3), and sodium orthophosphate-neutral protease treatment (S4) on the structural characteristics and flavor components of extruded corn flour (PCF) using scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, headspace solid phase microextraction, and gas chromatography mass spectrometry. The results showed that the extruded corn flour treated by these four methods exhibited an A-type crystal structure without the formation or introduction of any new chemical bonds or functional groups. The pores and cracks on the surface of starch microparticles significantly increased. Among them, the sodium orthophosphate+neutral protease treated powder had more surface pores and larger cracks than other samples. A total of 130 volatile components were identified by gas chromatography-mass spectrometry, including neutral protease treatment powder (57) > sodium orthophosphate+neutral protease treatment powder (46) > xanthan gum dry heat treatment powder (44) > PCF (41) > sodium orthophosphate heat treatment powder (40). ROAV analysis showed that the key flavor substances of extruded corn flour were mainly ketones. After different treatments, the overall flavor of the powder slightly differed, mainly aldehydes, with grass, orange, and fat flavor. The present study results could provide a theoretical basis to improve the flavor of blended grain powder.

Atrial septal aneurysm (ASA) is defined as excursion of the atrial septum exceeding 10 mm beyond the atrial septum into the right or left atrium, or a combined total excursion of 15 mm on the right and left sides during the cardiac cycle. According to previous studies, 20–40% of patent foramen ovale (PFO) cases are accompanied by ASAs. ASA is associated with the presence of PFO, left atrial dysfunction, cryptogenic stroke, migraine, and arterial embolism, thus making closure of PFO in patients with concomitant ASA necessary but challenging. The anatomy of ASAs associated with PFO has crucial effects on complications after the closure procedure; therefore, several factors must be considered. Herein, we review the clinical implications of concomitant PFO and ASA; discuss the complications occurring after the closure procedure; and provide practical guidance for the closure of concomitant PFO and ASA.

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.

Abstract Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from insulin secretion defects or insulin resistance. The global incidence of DM has been gradually increasing due to improvements in living standards and changes in dietary habits, making it a major non-communicable disease that poses a significant threat to human health and life. The pathogenesis of DM remains incompletely understood till now, and current pharmacotherapeutic interventions are largely inadequate, resulting in relapses and severe adverse reactions. Although DM is not explicitly mentioned in traditional Chinese medicine (TCM) theory and clinical practice, it is often classified as “Xiaoke” due to similarities in etiology, pathogenesis, and symptoms. With its overall regulation, multiple targets, and personalized medication approach, TCM treatment can effectively alleviate the clinical manifestations of DM and prevent or treat its complications. Furthermore, TCM exhibits desirable therapeutic effects with minimal side effects and a favorable safety profile. This paper provides a comprehensive comparison and contrast of Xiaoke and DM by examining the involvement of TCM in their etiology, pathogenesis, treatment guidelines, and other relevant aspects based on classical literature and research reports. The current TCM experimental research on the treatment of DM by lowering blood glucose levels also be generalized. This innovative focus not only illuminates the role of TCM in DM treatment, but also underscores the potential of TCM in DM management.

Abstract The association between antidepressant continuation during pregnancy and postpartum mental health in women with obsessive-compulsive disorder (OCD) is uncertain. We identified 1317 women with live-birth singleton pregnancies and having outpatient/inpatient visits for OCD in the 4 years pre-pregnancy from the Danish registries. We defined three groups based on antidepressant prescriptions filled in the 2 years before pregnancy to delivery: (i) unexposed (n = 449); (ii) discontinuers (n = 346), i.e., with pre-pregnancy antidepressant fills only; (iii) continuers (n = 522), i.e., with antidepressant fills before and during pregnancy. We estimated crude and propensity score weighted hazard ratio (HRs) of postpartum visit for OCD and mood/anxiety disorders using Cox proportional hazard models. In weighted analyses, we found no difference in the probability of a postpartum visit for OCD or MADs with antidepressant continuation compared to unexposed and discontinuers. The likelihood of a postpartum OCD visit was higher in pregnancies having only one prescription fill during pregnancy compared to unexposed (HR = 3.44, 95% CI: 1.24, 9.54) or discontinuers (HR = 2.49, 95% CI: 0.91, 6.83). Continuers in pregnancy without antidepressant fill in the first three months postpartum had higher probability for postpartum visit for mood/anxiety disorders compared to discontinuers (HR = 3.84, 95% CI: 1.49, 9.92). Among pregnant women with pre-existing OCD, we found similar probabilities of a postpartum visit for OCD or mood/anxiety disorders in antidepressant continuers compared to unexposed and discontinuers. Continuers with a single prescription fill during pregnancy or no fill postpartum may have higher risks for these outcomes. Our findings highlight the importance of continuity of treatment throughout the perinatal period.

Abstract Introduction The prognosis of anti‐MDA5 antibody‐positive dermatomyositis/clinically amyopathic dermatomyositis‐associated interstitial lung disease (MDA5‐DM/CADM‐ILD) is poor. This study was to evaluate the effect of serum soluble CD206 (sCD206), a biomarker of macrophage activation, on predicting the interstitial lung disease (ILD) deterioration and prognosis for MDA5‐DM/CADM‐ILD. Methods Forty‐one patients diagnosed with MDA5‐DM/CADM‐ILD were retrospectively included. The clinical data were analyzed. Serum sCD206 levels were measured in 41 patients and 30 healthy controls. The relation between sCD206 levels and ILD deterioration was assessed. Receiver operating characteristic (ROC) curve was generated to determine the optimal cut‐off value of sCD206 for predicting outcome. The association between sCD206 and survival was examined. Results The median serum sCD206 level in patients was significantly higher than healthy controls (464.1 ng/mL vs. 349.1 ng/mL, P = 0.002). In DM/CADM patients, the sCD206 level was significantly higher in patients with acute/subacute interstitial lung disease (AILD/SILD) than those with chronic interstitial lung disease (CILD) (539.2 ng/mL vs. 309.4 ng/mL, P = 0.005). The AUC of sCD206 was 0.885 for predicting mortality (95% CI 0.779–0.990). Patients were divided into two groups: sCD206 high level group (≥400 ng/mL) and sCD206 low level group (

The windowed synchronous averaging (WSA) is widely utilized for planetary structures. However, it cannot be applied for the fault detection of the planetary structure in the industrial robot rotate vector (RV) reducer. The robot usually works within a specified angle range, which causes the RV reducer rotates incompletely. To address this issue, an angle compensation local synchronous fitting scheme is proposed. To detect the localized planet gear fault in the RV reducer, the observed vibration is equi-angle resampled. And the synchronous interference contained in the resampled vibration is constructed and removed according to the angle compensation strategy. The residual data is used to construct the synthetic vibration of the planet gear. Then, the fault feature of the planet gear can be detected. Experiments on the RV reducer test rig under the robot running conditions support the effectiveness of the proposed scheme positively.

Abstract Purpose Early evaluation of the efficacy of first-line chemotherapy combined with bevacizumab in patients with colorectal cancer liver metastasis (CRLM) remains challenging. This study used 2-month post-chemotherapy spectral computed tomography (CT) to predict the overall survival (OS) and response of CRLM patients with bevacizumab-containing therapy. Method This retrospective analysis was performed in 104 patients with pathologically confirmed CRLM between April 2017 and October 2021. Patients were treated with 5-fluorouracil, leucovorin, oxaliplatin or irinotecan with bevacizumab. Portal venous phase spectral CT was performed on the target liver lesion within 2 months of commencing chemotherapy to demonstrate the iodine concentration (IoD) of the target liver lesion. The patients were classified as responders (R +) or non-responders (R −) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at 6 months. Multivariate analysis was performed to determine the relationships of the spectral CT parameters, tumor markers, morphology of target lesions with OS and response. The differences in portal venous phase spectral CT parameters between the R + and R − groups were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of spectral CT parameters. Results Of the 104 patients (mean age ± standard deviation: 57.73 years ± 12.56; 60 men) evaluated, 28 (26.9%) were classified as R + . Cox multivariate analysis identified the iodine concentration (hazard ratio [HR]: 1.238; 95% confidence interval [95% CI]: 1.089–1.408; P

Abstract Background Aging is known to exert an effect on liver regeneration, with the ability of liver to regenerate displaying a significant decline over time. Liver physiological parameters such as liver volume, blood flow, and metabolism, as well as the ability to regenerate after injury have all been shown to decrease at old age in humans and model systems, with a number of molecular mechanisms proposed to be involved, including DNA methylation-dependent genome remodeling. To address how changes in DNA methylation mediate the adverse aging effect on liver regeneration, we searched for differentially methylated genomic regions (DMRs) in mouse livers co-regulated by aging and regeneration and determined their associated genes and enriched pathways. Results DMRs were identified using whole-genome bisulfite sequencing (WGBS). Pathway analysis of aging DMR-mapped genes revealed two distinct phases of aging, 2-to-8 and 8-to-16 months old (m/o). Regenerative DMR-mapped differentially expressed genes (DEGs) were enriched in pathways controlling cell proliferation and differentiation. Most DMRs shared by both aging and regeneration changed in the same methylation direction between 2 and 8 m/o but in the opposite direction between 8 and 16 m/o. Regenerative DMRs inversely affected by aging during 8-to-16 m/o were found in the promoter/gene regions of 12 genes. Four regenerative DEGs were synchronously regulated by early aging and inversely regulated by mid-to-late aging DMRs. Lead DMR-mapped genes were validated by their expression profiles in liver aging and regeneration. Conclusions Our study has uncovered new DMRs and gene targets inversely affected by liver aging and regeneration to explain the adverse aging effect on liver regeneration. These findings will be of fundamental importance to understand the epigenomic changes underlying the biology of aging on liver regeneration.

BackgroundThe measurement of the coping difficulties of parents of premature infants after discharge provides objective data for nurses to prepare infants for discharge. However, no Chinese scale has been developed to measure parents’ coping difficulties after their premature infants are discharged.AimTo translate the parent version of the Post-Discharge Coping Difficulty Scale (Ped-PDCDS) from English to Chinese and test the reliability and validity of the Chinese version in parents of premature infants.MethodsA multicenter cross-sectional study of 356 parents of premature infants was conducted. The scale was symmetrically translated. Validity was evaluated in terms of content, construct, discriminant, and convergent validities. Reliability was assessed in terms of internal consistency, split-half reliability, and test–retest reliability.ResultsThe Chinese Ped-PDCDS finally contained 11 items. Exploratory and confirmatory factor analyses results showed that the Chinese Ped-PDCDS had three dimensions, and the convergent and discriminant validities of the scale was satisfactory. The overall reliability, split-half reliability, and test–retest reliability of the scale was 0.85, 0.92, and 0.84, respectively.ConclusionThe Chinese Ped-PDCDS has adequate psychometric properties, and is an easy and appropriate instrument for measuring parents’ difficulty in coping with premature infants.

The pathogenesis of liver in patients with hepatitis B virus-associated acute chronic liver failure (HBV-ACLF) remains largely unknown. We aimed to elucidate the molecular mechanism underlying the pathogenesis of liver in HBV-ACLF patients by using multiple approaches including transcriptome analysis. We performed transcriptomic sequencing analysis on the liver of HBV-ACLF patients (n = 6), chronic hepatitis B (n = 6), liver cirrhosis (n = 6) and normal control (n = 5), then explored the potential pathogenesis mechanism in liver specimen from another 48 subjects and further validated the molecular and cellular mechanisms using THP-1 cells. RNA-sequencing data analysis indicated that, among the genes up-regulated in HBV-ACLF, genes related to inflammatory response and chemotaxis accounted for a large proportion of the total DEGs. A number of key chemokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8) and NF-ĸB pathway were identified to be robust in the liver samples from HBV-ACLF patients. Interestingly, cylindromatosis (CYLD) was found to be downregulated in the liver of HBV-ACLF patients, in line with the well-established role of CYLD in regulating most of the chemokines and pro-inflammatory cytokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8, IL-6, IL-1β) via inhibition of NF-ĸB. Indeed, the knockdown of CYLD resulted in sustained activation of NF-ĸB in macrophages and enhanced chemokines and inflammatory cytokines production, which in turn enhanced chemotactic migration of neutrophil, monocyte, T lymphocytes, and NK cell. In conclusions, down-regulated CYLD aggravated inflammatory cell chemotaxis through enhancing NF-κB activation in HBV-ACLF patients, thereby participating in the pathogenesis of HBV-ACLF injury.

Abstract Background Early hepatocellular carcinoma (HCC) detection with non-invasive biomarkers remains an unmet clinical need. We aimed to construct a predictive model based on the pre-diagnostic levels of serum markers to predict the early-stage onset of HCC. Methods A total of 339 HCC patients (including 157 patients from Changzhou cohort and 182 patients from Wuxi cohort) were enrolled in our retrospective study. Levels of 25 baseline serum markers were collected. Propensity score matching (PSM) analysis was conducted to balance the distributions of patients’ gender, age, and the surveillance time between HCC group and control group. Then, Receiver operating characteristic (ROC) and Logistic regression analysis were performed to screen the independent predictive variables and construct a non-invasive predictive model. Subsequently, ROC curve and Kaplan–Meier (K–M) curve were used to evaluate the predictive values of the model. Clinical net benefit of the model was demonstrated by decision curve analysis (DCA) and clinical impact curve. Results Five independent predictive variables for HCC onset and two general characteristics of patients (age and gender) were incorporated into the score model. ROC and DCA curves showed that the score model had better predictive performance in discrimination and clinical net benefit compared with single variable or other score systems, with the area under the curve (AUC) of 0.890 (95% CI 0.856–0.925) in Changzhou cohort and 0.799 (95% CI 0.751–0.849) in Wuxi cohort. Meanwhile, stratification analysis indicated that the score model had good predictive values for patients with early tumor stage (AJCC stage I) or small tumors (

Abstract Background Long noncoding RNAs (lncRNAs) are emerging as the important regulators involving in growth and development as well as stress response in plants. However, current lncRNA studies were mainly performed at the individual level and the significance of it is not well understood in wheat. Results In this study, the lncRNA landscape of wheat spike was characterized through analysing a total of 186 spike RNA-seq datasets from 93 wheat genotypes. A total of 35,913 lncRNAs as well as 1,619 lncRNA-mRNA pairs comprised of 443 lncRNAs and 464 mRNAs were obtained. Compared to coding genes, these lncRNAs displayed rather low conservation among wheat and other gramineous species. Based on re-sequencing data, the genetic variations of these lncRNA were investigated and obvious genetic bottleneck were found on them during wheat domestication process. Furthermore, 122 lncRNAs were found to act as ceRNA to regulate endogenous competition. Finally, association and co-localization analysis of the candidate lncRNA-mRNA pairs identified 170 lncRNAs and 167 target mRNAs significantly associated with spike-related traits, including lncRNA.127690.1/TraesCS2A02G518500.1 (PMEI) and lncRNA.104854.1/TraesCS6A02G050300.1 (ATG5) associated with heading date and spike length, respectively. Conclusions This study reported the lncRNA landscape of wheat spike through the population transcriptome analysis, which not only contribute to better understand the wheat evolution from the perspective of lncRNA, but also lay the foundation for revealing roles of lncRNA playing in spike development.

Abstract Postpartum depression (PPD) is a serious condition associated with potentially tragic outcomes, and in an ideal world PPDs should be prevented. Risk prediction models have been developed in psychiatry estimating an individual’s probability of developing a specific condition, and recently a few models have also emerged within the field of PPD research, although none are implemented in clinical care. For the present study we aimed to develop and validate a prediction model to assess individualized risk of PPD and provide a tentative template for individualized risk calculation offering opportunities for additional external validation of this tool. Danish population registers served as our data sources and PPD was defined as recorded contact to a psychiatric treatment facility (ICD-10 code DF32-33) or redeemed antidepressant prescriptions (ATC code N06A), resulting in a sample of 6,402 PPD cases (development sample) and 2,379 (validation sample). Candidate predictors covered background information including cohabitating status, age, education, and previous psychiatric episodes in index mother (Core model), additional variables related to pregnancy and childbirth (Extended model), and further health information about the mother and her family (Extended+ model). Results indicated our recalibrated Extended model with 14 variables achieved highest performance with satisfying calibration and discrimination. Previous psychiatric history, maternal age, low education, and hyperemesis gravidarum were the most important predictors. Moving forward, external validation of the model represents the next step, while considering who will benefit from preventive PPD interventions, as well as considering potential consequences from false positive and negative test results, defined through different threshold values.

Abstract Background Following lung cancer surgery, patients often experience severe symptoms which are not properly assessed at discharge. The aim of this study was to identify the clinical presentation at discharge and the influencing factors of postoperative symptoms in patients who have undergone lung cancer surgery. Methods This cross-sectional study analysed data from patients who participated in a prospective cohort study that enrolled patients who underwent lung cancer surgery at six tertiary hospitals in the People’s Republic of China, from November 2017 to January 2020. Patient symptoms at discharge were measured using the MD Anderson Symptom Inventory Lung Cancer module. The five core symptoms were defined according to ratings of moderate to severe symptoms (≥ 4 on a 0–10 scale). A multivariate linear regression model was used to identify the influencing factors of each symptom at discharge. Results Among the 366 participants, 51.9% were male and the mean (SD) age was 55.81 (10.43) years. At discharge, the core symptoms were cough (36.4%), pain (28.2%), disturbed sleep (26.3%), shortness of breath (25.8%), and fatigue (24.3%), and more than half of the participants (54.6%) had one to five of the core symptoms, with moderate to severe severity. A low annual income and the use of two chest tubes were significantly associated (P = 0.030 and 0.014, respectively) with higher mean scores of the core symptoms. Conclusion Though clinically eligible for discharge, more than half of the participants had severe symptoms at discharge after lung cancer surgery. Special attention should be given to patients who have two chest tubes after surgery and those who have a low annual income.

Summary With the rapid development of synthetic biology, the oleaginous yeast Yarrowia lipolytica has become an attractive microorganism for chemical production. To better optimize and reroute metabolic pathways, we have expanded the CRISPR‐based gene expression toolkit of Y. lipolytica. By sorting the integration sites associated with high expression, new neutral integration sites associated with high expression and high integration efficiency were identified. Diverse genetic components, including promoters and terminators, were also characterized to expand the expression range. We found that in addition to promoters, the newly characterized terminators exhibited large variations in gene expression. These genetic components and integration sites were then used to regulate genes involved in the lycopene biosynthesis pathway, and different levels of lycopene production were achieved. The CRISPR‐based gene expression toolkit developed in this study will facilitate the genetic engineering of Y. lipolytica.

Abstract Fibrosing interstitial lung disease (ILD) can cause high mortality and sensitive evaluation of fibrosing ILD could be critical. The aim of this study is to develop a scoring system to predict prognosis of fibrosing ILD. 339 patients with fibrosing ILD were enrolled as a derivation cohort. Cox multiple regression analysis indicated that smoking history (HR = 3.826, p = 0.001), age(HR = 1.043, p = 0.015), CEA(HR = 1.059, p = 0.049),CYFRA21-1(HR = 1.177, p = 0.004) and DLCO% predicted (HR = 0.979, p = 0.032) were independent prognostic factors for fibrosing ILD. The clinical scoring system for fibrosing ILD was established based on the clinical variables (age [A], CEA and CYFRA21-1 [C], DLCO% predicted [D], and smoking history [S]; ACDS). The area under the receiver operating characteristic curve (AUROC) of the scoring system for predicting prognosis of fibrosing ILD was 0.90 (95%CI: 0.87–0.94, p

IntorductionColoration is a prominent trait in fish that is closely linked to their market value. Fish exhibit a diverse range of body colors, making them an excellent model for studying molecular mechanisms underlying pigmentation. Although regulatory pathways involved in pigmentation have been extensively studied in model fish such as zebrafish and medaka, the presence of varying chromatophore types across different fish species suggests that fish pigmentation mechanisms are not fixed. Therefore, more studies should be conducted on non-model fish. Sinibrama taeniatus is an endemic fish in the upper Yangtze River that is highly valued for its ornamental and edible properties.MethodsIn this study, we identified three chromatophore types in S. taeniatus and investigated changes in body color, chromatophores, and pigments at different developmental stages. Subsequently, RNA-seq analysis revealed that retinol metabolism, thyroid hormone synthesis, purine metabolism, and pyrimidine metabolism pathway are closely associated with pigmentation.ResultsWeighted gene co-expression network analysis (WGCNA) identified several hub genes, including mitf, wnt 9a, wnt10b, wnt11, adcy5, edn1, adcy8, and rdh8, that may play an important role in pigmentation.DiscussionOverall, our findings provide valuable insights into the role of genes and pathways in fish pigmentation and offer useful information for body color-based molecular breeding programs in aquaculture.

Background Studies on the associations between maternal complications during pregnancy and childhood asthma are exclusively conducted in Western countries. The findings are mixed and may not be translated to other populations. We aimed to investigate the associations among the Chinese population and to determine whether the associations were mediated through pre-term birth, caesarean delivery, low birthweight and not breastfeeding in the first 6 months. Methods We conducted a retrospective cohort study of 166 772 children in Guangzhou, China. Information on maternal gestational hypertension, gestational diabetes and gestational anaemia during pregnancy was extracted from medical records. Ever-diagnosis of asthma in children aged 6–12 years was obtained by questionnaire. Logistic regression models and mediation analyses were used to estimate the adjusted odds ratios (aORs) and 95% confidence intervals for childhood asthma. Results Gestational hypertension, gestational diabetes and gestational anaemia during pregnancy were associated with an increased risk of ever-diagnosed childhood asthma: aOR 1.48 (95% CI 1.37–1.60), 1.71 (95% CI 1.65–1.78) and 1.34 (95% CI 1.26–1.45), respectively. A stronger association was observed for two or three gestational complications (aOR 2.02 (95% CI 1.93–2.16)) than one gestational complication (aOR 1.64 (95% CI 1.52–1.77)). The aOR for the three gestational complications was 1.35 (95% CI 1.26–1.45), 1.63 (95% CI 1.58–1.70) and 1.32 (95% CI 1.24–1.43), respectively, after controlling for the mediators, including pre-term birth, caesarean delivery, low birthweight and not breastfeeding in the first 6 months. Conclusions Gestational hypertension, gestational diabetes and gestational anaemia were associated with childhood asthma, and the associations were partially explained by the mediation effects.

Objective This study aims to reveal the use and management status of continuous glucose monitoring (CGM) in tertiary hospitals in China and to determine the potential factors affecting the application of CGM, based on which more effective solutions would be produced and implemented.Design An online, cross-sectional study was conducted from October 2021 to December 2021.Setting Eighty-three tertiary hospitals in China were involved.Participants Eighty-three head nurses and 281 clinical nurses were obtained.Outcome Current condition of CGM use and management, the factors that hinder the use and management of CGM, scores of current CGM use and management, as well as their influencing factors, were collected.Results Among the 83 hospitals surveyed, 57 (68.7%) hospitals used CGM for no more than 10 patients per month. Seventy-three (88.0%) hospitals had developed CGM standard operating procedures, but only 29 (34.9%) hospitals devised emergency plans to deal with adverse effects related to CGM. Comparably, maternal and children’s hospitals were more likely to have a dedicated person to assign install CGM than general hospitals (52.2% vs 26.7%). As for the potential causes that hinder the use and management of CGM, head nurses’ and nurses’ perceptions differed. Head nurses perceived patients’ limited knowledge about CGM (60.2%), the high costs of CGM and inaccessibility to medical insurance (59.0%), and imperfect CGM management systems (44.6%) as the top three factors. Different from head nurses, CGM operation nurses considered the age of CGM operators, the type of hospital nurses worked in, the number of patients using CGM per month and the number of CGM training sessions as potential factors (p

Abstract Background Postpartum depression (PPD) is the most common postpartum psychiatric disorder, affecting 11–15% of new mothers, and initiatives towards early identification and treatment are essential due to detrimental consequences. Family history of psychiatric disorders is a risk factor for developing psychiatric episodes outside the postpartum period, but evidence of the association between familial risk and PPD is not clear. Hence, the objective of this systematic review is to summarize the current literature on the association between family history of psychiatric disorders and PPD. Methods This protocol has been developed and reported according to the PRISMA-P guidelines for systematic reviews. A comprehensive literature search will be conducted in PubMed, Embase, and PsycINFO from inception of the databases, supplemented with citation tracking and reference screening of the included studies. Two independent authors will examine all retrieved articles for inclusion in two steps: title/abstract screening and full-text screening. Eligible studies are case-control and cohort studies reporting a risk estimate for the association between family history of psychiatric disorders and PPD. Studies will be assessed for risk of bias using the Newcastle-Ottawa Scale. The association between family psychiatry and PPD will be combined in a meta-analysis using a restricted maximum likelihood method (REML). Heterogeneity will be quantified using I2 and investigated through meta-regression, subgroup and sensitivity analyses, and publication bias will be evaluated via visual inspection of a funnel plot. The overall strength and quality of the findings will be evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. If meta-analysis is not possible, data will be synthesized narratively in text and tables. Discussion This systematic review will be the first to summarize current knowledge and present an overall estimate for the association between family history of psychiatric disorders and PPD. Evaluation of psychiatric family history as a PPD risk factor is essential to assist early identification of women at high risk of PPD in routine perinatal care. Systematic review registration PROSPERO ID: 277998 (registered 10th of September 2021).

Abstract Background Previous studies have shown that the monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a predictor of various diseases such as coronary heart disease, diabetic microangiopathy, and metabolic syndrome. However, there are few scientific reports on the correlation between MHR and serum uric acid. The objective of this report is to explore the relationship between MHR and serum uric acid in Chinese adults. Methods This cross-sectional study included 646 participants from southwest China who underwent a health examination at the Health Management Center of Deyang People’s Hospital. The examination included blood pressure readings, routine blood tests (lipid, fasting glucose, serum transaminase, and serum uric acid levels), and various standardized questionnaires. We employed a generalized additive model and smoothed curve fitting to explore the relationship between MHR and serum uric acid levels. We then performed subgroup analyses to investigate the robustness of this relationship. Results After adjusting for confounders (age, sex, body mass index, systolic blood pressure, diastolic blood pressure, aspartate transaminase, alanine aminotransferase, fasting glucose, total cholesterol, low-density lipoprotein, smoking, drinking, and exercise status), MHR was found to be positively correlated with serum uric acid levels (P

The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC–MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH.

Most low-grade oral epithelial dysplasia remains static or regress, but a significant minority of them (4–11%) advances to oral squamous cell carcinoma (OSCC) within a few years. To monitor the progression of epithelial dysplasia for early cancer detection, we investigated the expression profiles of nucleostemin (NS) and phospho-STAT3 (p-STAT3) in rodent and human samples of dysplasia and OSCCs. In a 4NQO-induced rat oral carcinogenesis model, the number and distribution of NS and p-STAT3-positive cells increased in hyperplastic, dysplastic, and neoplastic lesions compared to normal epithelium. In human samples, the NS signal significantly increased in high-grade dysplasia and poorly differentiated OSCC, whereas p-STAT3 was more ubiquitously expressed than NS and showed increased intensity in high-grade dysplasia and both well and poorly differentiated OSCC. Analyses of human dysplastic samples with longitudinally followed outcomes revealed that cells with prominent nucleolar NS signals were more abundant in low-grade dysplasia that advanced to OSCC in 2 or 3 years than those remaining static for 7–14 years. These results suggest that NS upregulation and STAT3 activation are early events in the progression of low-grade dysplasia to OSCC.

IntroductionCurrent guidelines recommended patent foramen ovale (PFO) occlusion as the preferred treatment for PFO-related cryptogenic stroke (CS); however, finding the causative foramen ovale remains challenging. This study aimed to identify predictors and establish a scoring system by assessing PFO morphology and stroke-related factors.MethodsBased on a prospective multicenter registered clinical trial, we compared data mainly derived from transesophageal echocardiography (TEE) and clinical history in patients with PFO-related CS and those without CS (non-CS) with incidental PFO. Subsequently, we explored independent predictors using logistic analysis, established a scoring system based on the results, and finally evaluated the scoring system using receiver operating characteristic (ROC) analysis and internal validation.Results75 patients with PFO-related CS and 147 non-CS patients were enrolled. Multivariate logistic analysis showed that the change in PFO height, large PFO, atrial septal aneurysm (ASA), and sustained right-to-left shunt (RLS) had independent relationships with CS. Based on the odds ratio value of each independent factor, a scoring system was built: change in PFO height ≥ 1.85 mm (3 points), large PFO (2 points), ASA (5 points), sustained RLS (2 points). 0–2 points correspond to low-risk PFO, 3–5 points medium-risk PFO, and 7–12 points high-risk PFO. ROC analysis showed an area under the curve of 0.80 to predict CS. The proportion of patients with CS is increasing based on these points.ConclusionsOur study screened out the change in PFO height as an independent predictor of CS. A simple and convenient scoring system can provide constructive guidance for identifying whether the PFO is causal and consequently selecting patients more likely to benefit from closure.

The effect of thermal changes on the physiology and behavior of fish is a major research focus in the face of ongoing global warming. There is little information about the effects of temperature increase on fish in the wild. However, the consequences of temperature increase on fish in controlled laboratory conditions can provide insights into what can be expected in the wild. Triplophysa bleekeri, a high-plateau fish, exhibits high sensitivity to high temperatures, suggesting it to be a good model to investigate the impact of temperature increase on fish. In this study, we analyzed the effect of gradual temperature increase on transcriptional and metabolic levels of T. bleekeri subjected to a gradual temperature change of 0.5°C/day until temperatures of 10°C, 13°C, 16°C, and 19°C were reached. Transcriptomics results of the liver, gut, spleen, and trunk kidney showed that metabolic pathways are widely involved in the response to increased temperatures in T. bleekeri. Lipidomics results further indicated that the lipid composition was altered by increased temperatures, and three lipids (PC 14:0e/22:1, PC 18:0e/22:5, and TAG 14:3-21:2-21:2) were identified as potential biomarkers of heat stress in T. bleekeri. Moreover, a decline in unsaturated fatty acid levels was observed in T. bleekeri under high temperatures. These results suggest that high temperatures modify the metabolomic pathways. Overall, our results help improve the understanding of physiological responses in fish to increased temperatures, and provide valuable information predicting the consequences of global warming on fish.

BackgroundAlthough associations of physical activity and smoking with mortality have been well-established, the joint impact of physical activity and smoking on premature mortality among elderly hypertensive population was still unclear. This study aimed to assess association of physical activity, smoking, and their interaction with all-cause and cardiovascular disease (CVD) mortality risk in elderly hypertensive patients.MethodsWe included 125,978 Chinese hypertensive patients aged 60–85 years [mean (SD) age, 70.5 (6.9) years] who had records in electronic health information system of Minhang District of Shanghai, China in 2007–2015. Cox regression was used to estimate individual and joint association of smoking and physical activity on all-cause and CVD mortality. Interactions were measured both additively and multiplicatively. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S).ResultsAmong 125,978 elderly hypertensive patients (median age 70.1), 28,250 deaths from all causes and 13,164 deaths from CVD were observed during the follow-up up to 11 years. There was an additive interaction between smoking and physical inactivity [RERI: all-cause 0.19 (95% CI: 0.04–0.34), CVD 0.28 (0.06–0.50); AP: all-cause 0.09 (0.02–0.16), CVD 0.14 (0.04–0.23); S: all-cause 1.21 (1.04–1.42), CVD 1.36 (1.06–1.75)], while the concurrence of both risk factors was associated with more than 2-fold risk of death [hazard ratio (HR): all-cause 2.10 (1.99–2.21), CVD 2.19 (2.02–2.38)].ConclusionOur study suggested that smoking and physical inactivity together may have amplified association on premature death compared to the sum of their individual associations, highlighting the importance of improving behavioral factors in combination and promoting a comprehensive healthy lifestyle in hypertensive elderly.

Plants have evolved diverse strategies to accommodate saline environments. More insights into the knowledge of salt stress regulatory pathways will benefit crop breeding. RADICAL-INDUCED CELL DEATH 1 (RCD1) was previously identified as an essential player in salt stress response. However, the underlying mechanism remains elusive. Here, we unraveled that Arabidopsis NAC domain-containing protein 17 (ANAC017) acts downstream of RCD1 in salt stress response, and its ER-to-nucleus transport is triggered by high salinity. Genetic and biochemical evidence showed that RCD1 interacts with transmembrane motif-truncated ANAC017 in the nucleus and represses its transcriptional activity. Transcriptome analysis revealed that genes associated with oxidation reduction process and response to salt stress are similarly dysregulated in loss-of-function rcd1 and gain-of-function anac017-2 mutants. In addition, we found that ANAC017 plays a negative role in salt stress response by impairing the superoxide dismutase (SOD) enzyme activity. Taken together, our study uncovered that RCD1 promotes salt stress response and maintains ROS homeostasis by inhibiting ANAC017 activity.

Zhongyong, a central theme of Confucian thought, refers to the “doctrine of the mean,” or the idea that moderation in all things is the optimal path. Despite considerable interest in the relationship between zhongyong and creativity, especially in China, studies of this relationship have not yielded consistent results. Based on a review of the literature, we hypothesized that this inconsistency arises from the dual nature of zhongyong itself, which has both a positive side, promoting creativity, and a negative side, inhibiting creativity. We also hypothesized that the negative side of zhongyong takes the form of excessive zhongyong. Indeed, the observations that every coin has two sides and that too much of a good thing is as bad as too little are core principles of zhongyong in traditional Chinese culture. To test these hypotheses, we conducted two empirical studies (measuring explicit and implicit zhongyong personality, respectively) to examine the relationships between positive and negative zhongyong and creativity (measured in terms of creative personality, divergent thinking, and convergent thinking). The results of both studies revealed an interaction between positive zhongyong and negative zhongyong, indicating that only a moderate level of zhongyong is conducive to creativity; both deficiency and excess are harmful. We discuss the implications of these results, suggesting that a zhongyong approach can help to clarify non-linear relationships between things, and recommending to re-assess the creativity of Chinese culture from a neutral and objective outlook. This paper deepens understanding of zhongyong and offers clear insights into creativity from an in-depth cultural perspective.

BackgroundsGrowth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear.MethodThe study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed.ResultsSerum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007).ConclusionsThe GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.

Peanut is an oil crop with important economic value that is widely cultivated around the world. It blooms on the ground but bears fruit underground. When the peg penetrates the ground, it enters a dark environment, is subjected to mechanical stress from the soil, and develops into a normal pod. When a newly developed pod emerges from the soil, it turns green and stops growing. It has been reported that both darkness and mechanical stress are necessary for normal pod development. In this study, we investigated changes in gene expression during the reverse process of peg penetration: developmental arrest caused by pod (Pattee 3 pods) excavation. Bagging the aerial pods was used to simulate loss of mechanical pressure, while direct exposure of the aerial pods was used to simulate loss of both mechanical pressure and darkness. After the loss of mechanical stress and darkness, the DEGs were significantly enriched in photosynthesis, photosynthesis–antenna proteins, plant–pathogen interaction, DNA replication, and circadian rhythm pathways. The DNA replication pathway was enriched by down-regulated genes, and the other four pathways were enriched by upregulated genes. Upregulated genes were also significantly enriched in protein ubiquitination and calmodulin-related genes, highlighting the important role of ubiquitination and calcium signaling in pod development. Further analysis of DEGs showed that phytochrome A (Phy A), auxin response factor 9 (IAA9), and mechanosensitive ion channel protein played important roles in geocarpy. The expression of these two genes increased in subterranean pods but decreased in aerial pods. Based on a large number of chloroplast-related genes, calmodulin, kinases, and ubiquitin-related proteins identified in this study, we propose two possible signal transduction pathways involved in peanut geocarpy, namely, one begins in chloroplasts and signals down through phosphorylation, and the other begins during abiotic stress and signals down through calcium signaling, phosphorylation, and ubiquitination. Our study provides valuable information about putative regulatory genes for peanut pod development and contributes to a better understanding of the biological phenomenon of geocarpy.