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【Objective】The soil environment of tobacco planting can be impacted by plastic film mulching, which affects the structure of the soil microbial community and the growth and development of flue-cured tobacco. The purpose of this study is to investigate the effect of a full growth period mulching on the physicochemical properties and bacterial community structure of tobacco planting soil.【Method】16S rDNA sequencing was applied to compare the differences in the structure and diversity of bacterial communities in different treatments by various analytical methods. The connection between soil physicochemical properties and bacterial communities was discovered through redundancy analysis (RDA) based on soil physicochemical properties.【Result】The output value of flue-cured tobacco was significantly increased by film mulching during the growth period. The yield was increased by 13.33%, 18.24%, and 21.36% by the double color film mulching (SY), black film mulching (HY), and white film mulching (BY) treatments, respectively, compared to the control (CK); Output value added was 20.26%, 15.87%, and 13.28%. At the same time, film mulching will also increase tobacco-planting soil temperature, total potassium, total phosphorus, total iron and effective copper contents, and decrease soil pH value, alkaline dissolved nitrogen, effective iron, total copper and total zinc contents. The contents of total phosphorus and available copper increased the most significantly, reaching 3.11%-27.33% and 4.76%-19.05%, respectively. The most significant decrease in alkali hydrolyzed nitrogen, available iron, and total zinc occurred at 10.45%-14.50%, 3.36%-13.43%, and 7.69%-10.01%, respectively. Plastic covering during the whole growth period has a certain negative impact on the abundance of bacterial communities. The abundance index Chao 1 of the control was significantly higher than the three mulching treatments and was 14.09%, 24.20%, and 24.81% higher than that of the white film mulching, double color film mulching, and black film mulching treatments, respectively. Redundancy analysis shows that the main soil physicochemical factors affecting the horizontal community structure of the bacterial phylum are soil temperature, alkaline nitrogen, available iron, total iron, available copper, and total copper content. Three shared genera with significantly different abundance from the control were present in the white film mulching and double color film mulching treatments, which belonged to three families in the phylum Proteobacteria: Sphingomonadaceae, Burkholderiaceae, and Xanthomonadaceae.【Conclusion】The full-life stage mulching cultivation will significantly affect the physicochemical properties and bacterial community structure of tobacco-planting soil, and improve the amount of output value of roasted tobacco, suitable for matching the color of the film is black and white bicolor film.

Abstract PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid β-oxidation and ketogenesis.

Abstract Background Triple-negative breast cancer (TNBC) is one of the most aggressive human cancers and has poor prognosis. Approximately 80% of TNBC cases belong to the molecular basal-like subtype, which can be exploited therapeutically by inducing differentiation. However, the strategies for inducing the differentiation of TNBC remain underexplored. Methods A three-dimensional (3D) morphological screening model based on a natural compound library was used to identify possible candidate compounds that can induce TNBC cell differentiation. The efficacy of rutaecarpine was verified using assays: RT-qPCR, RNA-seq, flow cytometry, immunofluorescence, SCENITH and label-free LC–MS/MS. The direct targets of rutaecarpine were identified through drug affinity responsive target stability (DARTS) assay. A xenograft mice model was also constructed to confirm the effect of rutaecarpine in vivo. Results We identified that rutaecarpine, an indolopyridoquinazolinone, induces luminal differentiation of basal TNBC cells in both 3D spheroids and in vivo mice models. Mechanistically, rutaecarpine treatment leads to global metabolic stress and elevated ROS in 3D cultured TNBC cells. Moreover, NAC, a scavenger of ROS, impedes rutaecarpine-induced differentiation of TNBC cells in 3D culture. Finally, we identified fumarate hydratase (FH) as the direct interacting target of rutaecarpine. The inhibition of FH and the knockdown of FH consistently induced the differentiation of TNBC cells in 3D culture. Conclusions Our results provide a platform for differentiation therapy drug discovery using 3D culture models and identify rutaecarpine as a potential compound for TNBC treatment.

Abstract Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.

Abstract Background Anastomotic leak following radical gastrectomy poses a significant risk to patients. Despite previous studies, effective methods for diagnosing anastomotic leaks after gastric cancer surgery remain elusive. In this study, we aimed to assess the overall burden of anastomotic leaks and investigate diagnostic factors, particularly radiological signs on postoperative computed tomography (CT), that may facilitate early detection. Methods We included a total of 70 gastric cancer patients who underwent curative gastrectomy and underwent CT examination post‐surgery. Among them, 35 patients with anastomotic leak were matched with 35 patients without anastomotic leak. We compared the rates of various types of postoperative complications between the two groups and conducted univariate and multivariate analyses to identify predictive variables for postoperative diagnosis. Results Patients with anastomotic leaks experienced significantly longer postoperative hospital stays and higher overall expenditures (p

Abstract SOX1, a well-known tumor suppressor, delays malignant progression in most cancer types. However, high expression of SOX1 in late-stage head and neck squamous cell carcinoma leads to poor prognosis. In this study, we show that SOX1 induces nasopharyngeal carcinoma (NPC) cells to enter a quiescent state. Using a model that mimics therapeutic resistance and tumor recurrence, a subpopulation of SOX1-induced NPC cells is refractory to paclitaxel, a cell cycle-specific chemotherapy drug. These cells maintain a quiescent state with decreased translational activity and down-regulated cell growth potential. However, once SOX1 expression is decreased, the NPC cells recover and enter a proliferative state. The chemotherapy resistance induced by SOX1 can not pass to next generation, as the cells that undergo re-proliferation become sensitive to paclitaxel again. Moreover, SOX1 directly binds to the promoter region of the MYC gene, leading to transcriptional suppression. When switching to a paclitaxel-free culture environment, the cells with decreased levels of SOX1 re-express MYC, resulting in increased abundance of proliferative cancer cells. Our study presents an evolutionary trade-off between tumor growth and chemoresistance orchestrated by SOX1-MYC in NPC. Basing on the dynamic role of SOX1 in different stages of cancer development, SOX1 would be regarded as a “tumor hypnotist”.

Abstract Background Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC. Methods In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1. Results From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7–14.0 months). The CBR was 71.7% (95% CI, 57.7–83.2%), and the objective response rate was 64.2% (95% CI, 49.8–76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7–18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event. Conclusions Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities. Trial registration ClinicalTrials.gov, NCT04407988.

Abstract. Background:. Endocrine therapy (ET) and ET-based regimens are the preferred first-line treatment options for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HR+/HER2– MBC), while chemotherapy (CT) is commonly used in clinical practice. The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2– MBC. Methods:. Patients diagnosed with HR+/HER2–MBC between January 1st, 1996 and September 30th, 2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database. The initial and maintenance first-line treatment, progression-free survival (PFS), and overall survival (OS) were analyzed. Results:. Among the 1877 included patients, 1215 (64.7%) received CT and 662 (35.3%) received ET as initial first-line treatment. There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population (PFS: 12.0 vs. 11.0 months, P = 0.22; OS: 54.0 vs. 49.0 months, P =0.09) and propensity score matched population. For patients without disease progression after at least 3 months of initial therapy, maintenance ET following initial CT (CT-ET cohort, n = 449) and continuous schedule of ET (ET cohort, n = 527) had longer PFS than continuous schedule of CT (CT cohort, n = 406) in the total population (CT-ET cohort vs. CT cohort: 17.0 vs. 8.5 months; P

Abstract Background Panax ginseng is a perennial herb and one of the most widely used traditional medicines in China. During its long growth period, it is affected by various environmental factors. Past studies have shown that growth-regulating factors (GRFs) and GRF-interacting factors (GIFs) are involved in regulating plant growth and development, responding to environmental stress, and responding to the induction of exogenous hormones. However, GRF and GIF transcription factors in ginseng have not been reported. Results In this study, 20 GRF gene members of ginseng were systematically identified and found to be distributed on 13 chromosomes. The ginseng GIF gene family has only ten members, which are distributed on ten chromosomes. Phylogenetic analysis divided these PgGRFs into six clades and PgGIFs into two clades. In total, 18 of the 20 PgGRFs and eight of the ten PgGIFs are segmental duplications. Most PgGRF and PgGIF gene promoters contain some hormone- and stress- related cis-regulatory elements. Based on the available public RNA-Seq data, the expression patterns of PgGRF and PgGIF genes were analysed from 14 different tissues. The responses of the PgGRF gene to different hormones (6-BA, ABA, GA3, IAA) and abiotic stresses (cold, heat, drought, and salt) were studied. The expression of the PgGRF gene was significantly upregulated under GA3 induction and three weeks of heat treatment. The expression level of the PgGIF gene changed only slightly after one week of heat treatment. Conclusions The results of this study may be helpful for further study of the function of PgGRF and PgGIF genes and lay a foundation for further study of their role in the growth and development of Panax ginseng.

BackgroundCurrently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA.MethodsWe retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism.ResultsOur findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA (P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (ORIVW: 0.622, 95% CI: 0.438–0.883, FDR = 0.045) and elevated serum levels of X-11538 (ORIVW: 0.442, 95% CI: 0.250–0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections (Vibrio cholerae and Helicobacter pylori) as well as the mTOR signaling pathway.ConclusionIn conclusion, our study demonstrates that Family Rikenellaceae and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process.

Agricultural drainage from catchment greatly impacts water quality in the hilly area due to high nitrogen concentrations in the central basin of Sichuan Province, China. The original ecological ditches have proven effective in removing associated nutrient loads, but their nitrogen removal efficiency is limited by the elevated nitrogen levels of overland flow and subsurface flow. Field experiments were conducted to optimize the drainage network to enhance the performance of ecological ditches and enhance nitrogen removal efficiency in hilly regions. The results suggested that ecologically permeable dam ditches exhibited superior total nitrogen (TN) and total phosphorus (TP) removal efficiencies compared to single dams, multiple dams, and ecological intercept dams. Specifically, in single, multiple, and ecological intercept dams, TN removal was 20.2 %, 12.7 %, and 2.5 % higher, respectively, while TP removal was 18.2 %, 10.3 %, and 3.7 % higher, respectively. The TN removal efficiency by the Hydrocotyle verticillate and Iris pseudacorus L. ditch was 15.8 % and 2.3 % higher than that of the Myriophyllum verticillatum L. and Hydrocotyle verticillata and Hydrocotyle verticillata and Thalia dealbata Fraser, respectively. The TP removal efficiency in Hydrocotyle verticillata and Thalia dealbata Fraser ditch was 11.4 % and 3.5 % higher than that in Myriophyllum verticillatum L. and Hydrocotyle verticillata and Hydrocotyle verticillate and Iris pseudacorus L., respectively. The soil bed ditch demonstrated superior TN and TP removal efficiencies, with rates of 15.2 % and 11.3 %, respectively, compared to the pebble bed and mudstone bed (2.9 % and 3.4 %, respectively). Therefore, the original ecological ditch was reinforced through a combination of fine-textured soil substrates, native emergent plants with large biomass and ecologically permeable dams to enhance the removal efficiencies of TN and TP in agricultural drainage. Following reinforcement and evaluation in 2020, the removal efficiencies of TN, TP, ammonia nitrogen (AN) and nitrate nitrogen (NN) in the strengthened ecological ditches increased to 58.1 %, 56.5 %, 56.8 % and 54.2 %, respectively. In this study, a scientific foundation for enhancing the efficacy of ecological ditches in mitigating nonpoint source pollution from agricultural drainage in mountainous and hilly regions of subtropical and developing countries is established.

BackgroundThis meta-analysis investigated the influence of exercise on cognitive function in people living with diabetes.MethodsStringent criteria for literature inclusion and exclusion were defined. Searches were conducted across four English databases to gather randomized controlled trials investigating exercise interventions for cognitive function in people living with diabetes. Outcome indicators from 1193 subjects across 12 articles were analyzed using RevMan 5.4 software.ResultsExercise intervention demonstrated the ability to mitigate cognitive decline in people living with diabetes, with a combined effect size (standardized mean difference) of 0.91, 95% CI: 0.28, 1.54, P < 0.00001. The intervention effect showed significant modulation by intervention content (I2 = 95%), intervention duration (I2 = 95%), intervention frequency (I2 = 95%), and intervention cycle (I2 = 96%). Among these factors, multi-component exercise, sessions >40 minutes, exercise frequency >4 times per week, and sustained exercise for >6 months were paramount, all with P < 0.05.ConclusionExercise intervention emerges as a viable strategy for delaying cognitive decline in people living with diabetes. Its efficacy is subject to modulation by various variables. Optimal intervention includes multi-component exercise, individual sessions lasting 40-60 minutes, exercising >4 times a week, and continuous exercise for over 6 months.

IntroductionHealth literacy is linked to the health status of older adults and is a critical component in achieving active aging. This study to characterize the current health literacy status among older adults in combined medical and nursing care institutions, as well as the factors that influenced this status.MethodsThis cross-sectional study used a convenience sampling method to select 740 older adults who were in 16 combined medical and nursing care institutions in Chengdu, China, from July 2022 to June 2023, using the Health Literacy Management Scale, the Social Support Rating Scale, and the Short Form-36 Health Survey.ResultsThe results showed a health literacy score of 75.25 ± 12.33, the percentage of older adults with basic health literacy was 6.33%, a social support score of 37.37 ± 6.10, and a health-related quality of life score of 55.34 ± 15.48. Factors influencing health literacy included age, educational level, previous occupation, family size, monthly per capita household income, and health-related quality of life.DiscussionHealth literacy is an essential factor in improving the health status of older adults. Relevant departments should therefore improve health education and health promotion interventions for older adults in combined medical and nursing care institutions to improve health literacy.

Humic acid (HA) has been used as an important component in biostimulant formulations to enhance plant tolerance to salt stress, but the mechanisms underlying are not fully understood. This study was to investigate the physiological and molecular mechanisms of HA’s impact on salt stress tolerance in perennial ryegrass (Lolium perenne L.). The two types of HA were extracted from weathered coal samples collected from Wutai County (WTH) and Jingle County (JLH) of Shanxi Province, China. The grass seedlings subjected to salt stress (250 mM NaCl) were treated with HA solutions containing 0.01% WTH (W/V) or 0.05% JLH (W/V), respectively. The HA treatments improved leaf photosynthetic rate (Pn), transpiration rate (Tr), and stomatal conductance (Gs) and reduced leaf oxidative injury (lower malondialdehyde content) and Pro and intercellular CO2 concentrations in salt-stressed perennial ryegrass. The HA treatments also reversed the decline in antioxidative enzymes ascorbate peroxidase (APX), catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) activity and improved growth and anti-senescence hormones indole-3-acetic acid (IAA) and brassinosteroid (BR). The HA treatments reduced the relative expression of P5CS and its downstream products proline (Pro) and the stress defense hormones abscisic acid (ABA), salicylic acid (SA), jasmonic acid (JA), and polyamines (PA). The results of this study indicate that the application of HAs may improve salt stress tolerance by regulating P5CS gene expression related to osmotic adjustment and increasing the activity of antioxidant enzymes and anti-senescence hormones in perennial ryegrass.

IntroductionThe BAHD (benzylalcohol O-acetyl transferase, anthocyanin O-hydroxycinnamoyl transferase, N-hydroxycinnamoyl anthranilate benzoyl transferase and deacetylvindoline 4-O-acetyltransferase), has various biological functions in plants, including catalyzing the biosynthesis of terpenes, phenolics and esters, participating in plant stress response, affecting cell stability, and regulating fruit quality. MethodsBioinformatics methods, real-time fluorescence quantitative PCR technology, and ultra-high-performance liquid chromatography combined with an Orbitrap mass spectrometer were used to explore the relationship between the BAHD gene family and malonyl ginsenosides in Panax ginseng. ResultsIn this study, 103 BAHD genes were identified in P. ginseng, mainly distributed in three major clades. Most PgBAHDs contain cis-acting elements associated with abiotic stress response and plant hormone response. Among the 103 genes, 68 PgBAHDs are WGD (whole-genome duplication) genes. The significance of malonylation in biosynthesis has garnered considerable attention in the study of malonyltransferases. The phylogenetic tree results showed 34 PgBAHDs were clustered with genes that have malonyl characterization. Among them, seven PgBAHDs (PgBAHD4, 45, 65, 74, 90, 97, and 99) showed correlations > 0.9 with crucial enzyme genes involved in ginsenoside biosynthesis and > 0.8 with malonyl ginsenosides. These seven genes were considered potential candidates involved in the biosynthesis of malonyl ginsenosides. DiscussionThese results help elucidate the structure, evolution, and functions of the P. ginseng BAHD gene family, and establish the foundation for further research on the mechanism of BAHD genes in ginsenoside biosynthesis.

Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic–metabolic feedback loop between the epithelial–mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2–ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.

Background Circular RNAs (circRNAs) are promising biomarkers and therapeutic targets for acute kidney injury (AKI). In this study, we investigated the mechanism by which circRNA itchy E3 ubiquitin protein ligase (circ-ITCH) regulates sepsis-induced AKI.Methods A sepsis-induced AKI mouse model was created using LPS induction and circ-ITCH overexpression. Circ-ITCH levels were confirmed via RT-qPCR. Kidney tissue changes were examined through various stains and TUNEL. Enzyme-linked immunosorbent assay (ELISA) gauged oxidative stress and inflammation. Mitochondrial features were studied with electron microscopy. RT-qPCR and western blotting assessed mitochondrial function parameters. Using starBase, binding sites between circ-ITCH and miR-214-3p, as well as miR-214-3p and ABCA1, were predicted. Regulatory connections were proven by dual-luciferase assay, RT-qPCR, and western blotting.Results Circ-ITCH expression was downregulated in LPS-induced sepsis mice. Overexpression of circ-ITCH ameliorates indicators of renal function (serum creatinine [SCr], blood urea nitrogen [BUN], neutrophil gelatinase-associated lipocalin [NGAL], and kidney injury molecule-1 [Kim-1]), reduces renal cell apoptosis, mitigates oxidative stress markers (reactive oxygen species [ROS] and malondialdehyde [MDA]), and diminishes inflammatory markers (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF-α]). Moreover, circ-ITCH overexpression alleviated mitochondrial damage and dysfunction. Furthermore, circ-ITCH acts as a sponge for miR-214-3p, thereby upregulating ABCA1 expression. In addition, the miR-214-3p inhibitor repressed oxidative stress, inflammation, and mitochondrial dysfunction, which was reversed by circ-ITCH knockdown. Further cellular analysis in HK-2 cells supported these findings, highlighting the protective role of circ-ITCH against sepsis-induced AKI, particularly through the miR-214-3p/ABCA1 axis.Conclusion The novel circ-ITCH/miR-214-3p/ABCA1 pathway plays an essential role in the regulation of oxidative stress and mitochondrial dysfunction in sepsis-induced AKI.

Huizhou garden is a branch of the gardening system in the regions south of the Yangtze River in China, which has not been studied by many researchers because there are few relics. Located in Xiuning County, Huangshan City, Anhui Province, Zuoyin Garden is a garden of the Ming Dynasty, which was built by Wang tingne, a Huizhou merchant, during the Wanli period. There is only a water source at the current base, as the ground buildings were destroyed. Wang Tingne published a long scroll print of Huizhou, the Garden View of Huancui Hall to depict the complete landscape. The purpose of this paper is to bring academic attention to the heritage of Huizhou gardens through the restoration of Zuoyin Garden.It is also expected that the restoration results will become the design basis and reference for relevant construction units to reconstruct Zuoyin Garden, and can also provide inspiration for the conservation and research of local gardens. In this paper, the main buildings that are depicted most clearly in the print were studied.The scientific structure determination, dimension speculation and courtyard layout were carried out according to the method of graphics and text derivation and the ancient technical architectural laws based on the gardening background, and several perspective renderings were modeled. Through the restoration study, it is found that the Zuoyin Garden has the characteristics of superior site selection, regular layout, elegant courtyard and gorgeous architectural decoration, and the natural landscape environment and humanistic environment of Huizhou has nurtured the unique Huizhou garden culture, which indicates that Huizhou garden is also an excellent garden cultural heritage and expands the research content of garden in the regions south of the Yangtze River in China.

Coal seam water injection can effectively inhibit gas gushing in the process of coal mining, and its inhibition effect mainly depends on the wetting characteristics of coal seam. The chemical structure of coal is one of the important factors affecting the wettability of coal. In order to study the relationship between the functional groups of medium and low rank coal and its wettability, the coal quality characteristics of typical medium and low rank coal samples were analyzed, and the parameters of different coal samples were obtained by Nicolet iN10 Fourier Transform microscopic infrared spectrometer. In this paper, the size of the contact Angle of deionized water at the solid-liquid-gas junction on the coal surface is used to characterize the wettability of coal. JC2000D contact Angle measuring instrument is used to obtain the contact Angle of different coal samples. Zeta potential can reflect wettability and ionization degree of coal surface functional groups, so as to establish the relationship between hydrophilic functional groups (hydroxyl functional groups, other oxygen-containing functional groups), contact Angle and Zeta potential of coal samples. The experimental results show that with the deepening of coal metamorphism, the strength of hydrophilic functional groups of coal samples decreases gradually, the peak height of hydrophilic functional groups of middle rank coal decreases by 0.13 compared with that of low rank coal, and the absorption peak area decreases by 58.91. The hydrophilic functional groups are negatively correlated with the contact Angle of coal samples, that is, the contact Angle decreases gradually with the increase of absorption peak intensity of hydrophilic functional groups, and the contact Angle decreases by 8.27 ° from middle rank coal samples to low rank coal samples. The relationship between hydrophilic functional groups and Zeta potential of coal samples shows a first-order exponential decay function, and the correlation coefficient is as high as 0.95. That is to say, the absolute value of Zeta potential increases gradually with the increase of absorption peak area of hydrophilic functional groups. The surface electronicity of coal samples is strong, and the hydrophilicity of coal is good. Among them, the hydroxyl functional group has a great influence on the wettability of coal, and the hydrogen bond formed by self-associating hydroxyl group is the main factor affecting the wettability of coal. Other oxygen-containing functional groups, such as carboxyl and ether bond hydrophilic functional groups, combine with water molecules under intermolecular force, showing strong vitality and improving the hydrophilicity of coal.

Abstract Purpose Bone marrow metastasis (BMM) is uncommon in breast cancer (BC), and early diagnosis is challenging. BMM lacks definitive treatment options and poses a great threat to the survival of patients. Herein, we investigated the clinical features, prognosis, and factors affecting the prognosis of BC patients with symptomatic BMM to help improve the understanding of this disease and provide effective diagnostic and treatment strategies. Methods Clinical data of 67 patients with BC and BMM were retrospectively analyzed for clinical characteristics, treatment, and prognosis of BMM. Univariate and multivariate analyses were performed to determine factors affecting overall survival following BMM (BMMOS). Results Among patients with BMM, 86.6% were diagnosed after bone metastasis (BM), while 13.4% were diagnosed simultaneously with BM. A total of 73.1%, 13.4%, and 13.4% of the patients had hormone receptor‐positive/human epidermal growth factor 2‐negative (HR+/HER2−) tumors, HER2+ tumors, and triple‐negative tumors, respectively. The most common symptoms of BMM were the coexistence of anemia and thrombocytopenia (26.9%), anemia (19.4%), and pancytopenia (17.9%). The median BMMOS was 7.6 months (95% CI, 3.9–11.3). Univariate and multivariate analyses showed that BMMOS was associated with platelet count

Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28–75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30–9.11) and 3.72 (95% CI, 1.91–5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58–0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).

Abstract Background COVID-19, the current global pandemic caused by SARS-CoV-2 infection, can damage the heart and lead to heart failure (HF) and even cardiac death. The 2',5'-oligoadenylate synthetase (OAS) gene family encode interferon (IFN)-induced antiviral proteins which is associated with the antiviral immune responses of COVID-19. While the potential association of OAS gene family with cardiac injury and failure in COVID-19 has not been determined. Methods The expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. The associated microRNAs (miRNAs) were explored from Targetscan and GSE104150. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database. Results The OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expressed genes (DEGs) in the two datasets were enriched in both cardiovascular disease and COVID-19 related pathways. The miRNAs-target analysis indicated that 10 miRNAs could increase the expression of OAS genes. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family especially estradiol. Conclusion OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19.

Aims: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. Methods and Results: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson’s trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). Conclusion: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

As a potential crop in saline-alkali land, the growth of switchgrass could also be threatened by salt stress. Promoting the growth of switchgrass under salt stress by humic acid has great significance in the utilization of saline-alkali land. In this study, a pot experiment was arranged to investigate the responses of photosynthetic and physicochemical characteristics of switchgrass to HA under salt stress. Results showed that humic acid increased the photosynthetic function of switchgrass and enhanced plant height by 41.1% and dry weight by 26.9% under salt stress. Correlation analysis showed that the membrane aquaporin gene PvPIP1, malondialdehyde, ascorbate peroxidase, abscisic acid, polyamine, and jasmonic acid were important factors affecting the photosynthetic function of switchgrass in this study. Meanwhile, HA reduced the content of malondialdehyde, indicating the alleviation of the membrane damage caused by salt stress. On the other hand, HA upregulated the relative expression of the PvPIP1 gene and activated ascorbate peroxidase, abscisic acid, polyamine, and jasmonic acid in switchgrass to resist salt stress. These improved the membrane stability and promoted the photosynthetic activity of switchgrass to enhance the plant’s tolerance against salt stress and growth. Results from this study are helpful to the efficient growing of switchgrass and the sustainable development of saline-alkali land.

Hemostatic disturbances after cardiac surgery can lead to excessive postoperative bleeding. Thromboelastography (TEG) was employed to evaluate perioperative coagulative alterations in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), investigating the correlation between factors concomitant with cardiac surgery and modifications in coagulation. Coagulation index as determined by TEG correlated significantly with postoperative bleeding at 24-72 h after cardiac surgery ( P

As the predominant immunosuppressive component within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) inhibit Natural Killer cell (NK cell) activity to promote tumor progression and immune escape; however, the mechanisms of cross-talk between CAFs and NK cells in gastric cancer (GC) remain poorly understood. In this study, we demonstrate that NK cell levels are inversely correlated with CAFs abundance in human GC. CAFs impair the anti-tumor capacity of NK cells by inducing ferroptosis, a cell death process characterized by the accumulation of iron-dependent lipid peroxides. CAFs induce ferroptosis in NK cells by promoting iron overload; conversely, decreased intracellular iron levels protect NK cells against CAF-induced ferroptosis. Mechanistically, CAFs increase the labile iron pool within NK cells via iron export into the TME, which is mediated by the upregulated expression of iron regulatory genes ferroportin1 and hephaestin in CAFs. Moreover, CAF-derived follistatin like protein 1(FSTL1) upregulates NCOA4 expression in NK cells via the DIP2A-P38 pathway, and NCOA4-mediated ferritinophagy is required for CAF-induced NK cell ferroptosis. In a human patient-derived organoid model, functional targeting of CAFs using a combination of deferoxamine and FSTL1-neutralizing antibody significantly alleviate CAF-induced NK cell ferroptosis and boost the cytotoxicity of NK cells against GC. This study demonstrates a novel mechanism of suppression of NK cell activity by CAFs in the TME and presents a potential therapeutic approach to augment the immune response against GC mediated by NK cells.

IntroductionClonorchis sinensis infection results in various complications in the liver and biliary systems and is a neglected tropical disease in Eastern Asia. In this study, we report that C. sinensis calcium-binding protein Cs16 activates host immune cells and induces immunopathology in liver.MethodsImmunohistochemistry was used to detect the localization of Cs16 in C. sinensis adult worms. ELISA was used to detect the serum levels of anti-Cs16 IgG antibody in infected humans and mice. Bile duct injection model was used to figure out the role of Cs16 in vivo. RT-qPCR and ELISA were used to detect the cytokine production from Cs16-treated BMMs in vitro. Seahorse assay was used to detect the metabolic pathway of Cs16-treated BMMs in vitro.ResultCs16 localizes in the tegument and gut of C. sinensis. Humans and mice with C. sinensis infection exhibited increased levels of anti-Cs16-specific antibody. Using the bile duct injection technique, we found that Cs16 induced obvious inflammation and hepatic necrosis in vivo. Cs16 treatment caused the upregulation of inflammatory cytokines in innate immune cells. Moreover, Cs16-treated monocytes relied more on the glycolytic metabolic pathway.DiscussionOur findings suggest that Cs16 is a potential pathogenic factor derived from C. sinensis adult worm. By reprogramming the metabolic pathway of innate immune cells, Cs16 triggers pro-inflammatory responses in the liver, and therefore, Cs16 is a potential target for the prevention and treatment of clonorchiasis.

Summary: Perioperative blood transfusion is costly and raises safety concerns. We developed and validated a model for predicting minor, moderate, or major transfusion given to patients during on-pump cardiac procedures based on two centers’ database. Model performance incorporating 7 variables on the development set had an AUC of 0.803 [95% CI, 0.790–0.815] for minor transfusion; moderate transfusion, giving an AUC of 0.822 (95% CI, 0.803–0.841); and major transfusion, giving an AUC of 0.813 (95% CI, 0.759–0.866). Model performance on the validation set had an AUC of 0.739 (95% CI 0.714–0.765), 0.730 (95% CI 0.702–0.758), and 0.713 (95% CI 0.677–0.749), respectively. A model based entirely on readily available electronic health records can accurately predict intraoperative minor, moderate, or major transfusion and provide individualized transfusion risk profiles before surgery among those on-pump cardiac surgical patients, and may help guide patient management.

As an activator and alarm signal for tumor innate immune therapy, manganese ions can activate the stimulator of interferon genes (STING) pathway directly or indirectly. However, due to their high positive charge, manganese ions cannot freely penetrate biological membranes, and it is challenging to target them to the cells. Liposomes have been widely used as an effective drug delivery system. Using metal ions as active carriers to establish a gradient is an effective way to load chemotherapy drugs, but its low delivery efficiency and significant degradation of effective drugs by lysosomes may result in reduced therapeutic effects. In this study, we constructed an active drug-loading liposome (LMD@LA) that enters cells through thiol-mediated endocytosis to encapsulate both the chemotherapy drug doxorubicin and manganese ions to achieve sustained manganese ion release. The combination of chemotherapy-induced immunogenic cell death and innate immune therapy with manganese ions was used to treat tumors. The liposome was able to reverse the immunosuppressive tumor microenvironment, reduce the resistance of B16F10 and 4T1 tumors to doxorubicin, and decrease the migration and invasion abilities of tumors by binding with lipoic acid.

Abstract There is evidence linking hand, foot and mouth disease (HFMD) to gut microbiota dysbiosis, and this relationship was corroborated in a large HFMD patient population in our previous study. Here, we present a bacterial 16S rRNA gene dataset from faecal samples of 713 individuals (254 HFMD patients, 459 healthy controls) aged 2 to 7 years residing in Heyuan and Jiangmen counties, Guangdong Province, southern China. Microbiome analysis indicated a significant increase in genus Prevotella, Cetobacterium, and Megamonas was observed in patients with HFMD, whereas a large increase in genus Bacteroides, Ruminococcus, and Faecalibacterium were seen in the control group. We also share the bioinformatic analytical pipeline for this analysis, from data preprocessing to data filtering and amplicon sequence variant (ASV) table generation. We expect that the dataset will be reprocessed, evaluated and fully analysed with various analysis methods to further elucidate the role of the gut microbiota in HFMD development.

Abstract Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis, which potentially facilitates progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptosis through its only receptor, c-Met. In addition to binding with HGF, c-Met also binds to Fas to form a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunostaining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we found that HGF secretion was significantly higher at 10 weeks post-DEN, the liver cirrhotic phase (LCP), than at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, differences in CD8+ T cell proliferation and apoptosis were noted between the two phases. Interestingly, staining and TUNEL assays revealed lower smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cells (HSCs), in the LFP group than in the LCP group, which suggested a beneficial correlation among HGF, CD8+ T cells and HSCs in improving the fibrotic load during damaged liver repair. In cultures, when met different concentrations of recombinant HGF (rHGF), phytohemagglutinin (PHA)-stimulated naive mouse splenic CD8+ T cells (pn-msCD8+ T cells) responded differently; as increases in rHGF increased were associated with decreases in the clonal numbers of pn-msCD8+ T cells, and when the rHGF dose was greater than 200 ng/mL, the clonal numbers significantly decreased. In the presence of 400 ng/mL rHGF, the death-inducing signaling complex (DISC) can be directly activated in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), as indicated by recruitment of FADD and caspase-8 because DISC forms via the recruitment of FADD and caspase-8, among others. These findings suggest that Fas-mediated apoptosis, may also indicate a regulatory role of HGF signaling in hepatic homeostasis.

Celastrol is a promising antitumor drug candidate, but the poor water solubility and cytotoxicity limit its clinical application. Herein, we synthesized a Celastrol (Cel)-chitosan oligosaccharide (CSO) conjugate (Cel-CSO) for drug delivery. Celastrol was conjugated to a CSO backbone via amide bond formation, which was verified by infrared spectrum (IR) analyses. The Cel-CSO contained ∼10 wt% of Celastrol showed excellent aqueous solubility (18.6 mg/mL) in comparation with the parent Celastrol. Cel-CSO significantly inhibited tumor growth, induced apoptosis, and effectively suppressed tumor metastasis in human pancreatic cancer cells (BxPC-3). While the cytotoxicity of Cel-CSO in hepatic cells (HL7702) was lower than that of the free Celastrol. Cel-CSO enhanced the anticancer efficacy, promoted the circulation time of Celastrol, and reduced the subacute toxicity, which indicated that CSO can be a promising Celastrol delivery system for pancreatic cancer therapy.

Intraoperative blood salvage (IBS) is a life support technology that uses a series of artificial devices to treat the recycled blood during surgery, which then is transfused back into the patients. Currently, it′s the key method for perioperative blood protection. With the continuous development of science and technology as well as the deepening of researches, it has been realized that the damage of autologous blood recycling to red blood cells can not be ignored. This paper reviews the current progress of IBS researches and their effects on RBC.

Abstract. Background:. Re-biopsy of metastasis in advanced breast cancer (ABC) has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity. This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression levels between primary and metastatic lesions. Methods:. We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018. The pathological diagnosis of biopsies, distribution of biopsy sites, and severe puncture complications at each site were collected. In addition, the inconsistency rates and related factors of ER, PR, and HER2 expression between primary and metastatic lesions were analyzed fully considering patients’ demographic profiles and disease characteristics. Results:. In total, 1670 cases of breast cancer (BC) patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment, producing 2019 histopathological specimens which were analyzed in the study. Pathological diagnosis showed that eight patients had benign pathological diagnoses, 11 patients had second primary malignant tumors but without recurrences of breast cancer, and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer. In 1173 patients who presented ER, PR, and HER2 expressions in primary and metastatic lesions, the inconsistency rates of ER, PR, and HER2 were 17.5% (205/1173), 31.3% (367/1173), and 13.9% (163/1173), respectively. The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level. Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax, no other severe puncture complications occurred in 1950 non-surgical rebiopsies. Conclusions:. The pathological diagnosis of metastasis re-biopsy of ABC was diverse, and the ER, PR, and HER2 expression levels were inconsistent between primary and metastatic lesions. Therefore, more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.

Abstract Background Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. Methods Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. Results High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. Conclusion DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.

Abdominal aortic aneurysms (AAAs) are characterized by localized dilation of the abdominal aorta. They are associated with several serious consequences, including compression of adjacent abdominal organs, pain, treatment-related financial expenditure. The main complication of AAA is aortic rupture, which is responsible for about 200,000 deaths per year worldwide. An increasing number of researchers are dedicating their efforts to study AAA, resulting in significant progress in this field. Despite the commendable progress made thus far, there remains a lack of established methods to effectively decelerate the dilation of aneurysms. Therefore, further studies are imperative to expand our understanding and enhance our knowledge concerning AAAs. Although numerous factors are known to be associated with the occurrence and progression of AAA, the exact pathway of development remains unclear. While asymptomatic at most times, AAA features a highly unpredictable disease course, which could culminate in the highly deadly rupture of the aneurysmal aorta. Current guidelines recommend watchful waiting and lifestyle adjustment for smaller, slow-growing aneurysms, while elective/prophylactic surgical repairs including open repair and endovascular aneurysm repair are recommended for larger aneurysms that have grown beyond certain thresholds (55 mm for males and 50 mm for females). The latter is a minimally invasive procedure and is widely believed to be suited for patients with a poor general condition. However, several concerns have recently been raised regarding the postoperative complications and possible loss of associated survival benefits on it. In this review, we aimed to highlight the current status of diagnosis and treatment of AAA by an in-depth analysis of the findings from literatures.

BackgroundObservational studies have suggested an association between obesity and iron deficiency anemia, but such studies are susceptible to reverse causation and residual confounding. Here we used Mendelian randomization to assess whether the association might be causal.MethodsData on single-nucleotide polymorphisms that might be associated with various anthropometric indicators of obesity were extracted as instrumental variables from genome-wide association studies in the UK Biobank. Data on genetic variants in iron deficiency anemia were extracted from a genome-wide association study dataset within the Biobank. Heterogeneity in the data was assessed using inverse variance-weighted regression, Mendelian randomization Egger regression, and Cochran's Q statistic. Potential causality was assessed using inverse variance-weighted, Mendelian randomization Egger, weighted median, maximum likelihood and penalized weighted median methods. Outlier SNPs were identified using Mendelian randomization PRESSO analysis and “leave-one-out” analysis.ResultsInverse variance-weighted regression associated iron deficiency anemia with body mass index, waist circumference, trunk fat mass, body fat mass, trunk fat percentage, and body fat percentage (all odds ratios 1.003–1.004, P ≤ 0.001). Heterogeneity was minimal and no evidence of horizontal pleiotropy was found.ConclusionOur Mendelian randomization analysis suggests that obesity can cause iron deficiency anemia.

Soil salinization is a major environmental stressor hindering global crop production. Hydropriming has emerged as a promising approach to reduce salt stress and enhance crop yields on salinized land. However, a better mechanisitic understanding is required to improve salt stress tolerance. We used a biochemical and metabolomics approach to study the effect of salt stress of hydroprimed maize to identify the types and variation of differentially accumulated metabolites. Here we show that hydropriming significantly increased catalase (CAT) activity, soluble sugar and proline content, decreased superoxide dismutase (SOD) activity and peroxide (H2O2) content. Conversely, hydropriming had no significant effect on POD activity, soluble protein and MDA content under salt stress. The Metabolite analysis indicated that salt stress significantly increased the content of 1278 metabolites and decreased the content of 1044 metabolites. Ethisterone (progesterone) was the most important metabolite produced in the roots of unprimed samples in response to salt s tress. Pathway enrichment analysis indicated that flavone and flavonol biosynthesis, which relate to scavenging reactive oxygen species (ROS), was the most significant metabolic pathway related to salt stress. Hydropriming significantly increased the content of 873 metabolites and significantly decreased the content of 1313 metabolites. 5-Methyltetrahydrofolate, a methyl donor for methionine, was the most important metabolite produced in the roots of hydroprimed samples in response to salt stress. Plant growth regulator, such as melatonin, gibberellin A8, estrone, abscisic acid and brassinolide involved in both treatment. Our results not only verify the roles of key metabolites in resisting salt stress, but also further evidence that flavone and flavonol biosynthesis and plant growth regulator relate to salt tolerance.

As a predominant ecosystem-providing area and distinctive landscape in arid regions, an oasis plays an important role in maintaining land stability, human production, and daily activities. Studying the dynamics of oasis and its driving factors is vital to supporting arid regions’ sustainable development. As a typical mountain–desert–oasis landscape, the Turpan–Hami (Tuha) Basin, located in Xinjiang, China, includes complex interactions among different land types. For this study, we revealed the spatio-temporal patterns and transition processes of the oasis using a complex network method between 1990 and 2020 in the Tuha Basin. In the oasis transition network, the degree value, betweenness centrality, and average path length were calculated to express the transition relationship, key oasis type, and oasis structural stability, respectively. Six factors related to climate change and human actives were selected to investigate the driving forces behind oasis transitions, including the average temperature and precipitation in the growing season, the total power of agricultural machinery (TAMP), the production of raw coal (PRC), the total output value of the plantation industry (TPI), and the population (Pop). Our results show that the oasis area of the Tuha Basin, including the natural oasis and artificial oasis, all grew from 1990 to 2020, with the natural oasis expanding more than the artificial oasis. The transitions between oasis types became more frequent as the area of oasis land types increased throughout the study period. Grassland acted as the most important oasis type in the network, with the highest betweenness centrality, but its importance declined due to the increasing complexity of the oasis transition network from 1990 to 2020. The transitions between oasis types became simpler, and the oasis structural stability decreased. Through driving force analysis, the oasis changes showed a positive correlation with the temperature (p-value < 0.05, r = 0.88), and urbanization and industrialization factors prompted transitions to built-up areas and cropland from grassland and shrubland. In summary, our results suggest that to create a harmonious symbiotic relationship between the natural environment in dryland and human activities, preventing grassland degradation and excessive reclamation of land cover is an available way. Meanwhile, the protection of shrubland and water resources is also important. This study provided reference and theory support for promoting the sustainable development of oases.

Over the past several years, Shenzhen’s air quality has significantly improved despite increased ground-level ozone (O3) and the challenges in reducing fine particulate matter (PM2.5). We investigated concentration trends, concurrent pollution features, and long-term exposure health risks to enhance our understanding of the characteristics of O3 and PM2.5 pollution. From 2016 to 2022, there was a decrease in PM2.5 levels, but an increase in O3. Additionally, the premature mortality attributed to long-term air pollution exposure decreased by 20.1%. High-O3-and-PM2.5 days were defined as those when the MDA8 O3 ≥ 160 μg m–3 and PM2.5 ≥ 35 μg m–3. Significantly higher levels of O3, PM2.5, nitrogen dioxide (NO2), OX (OX = O3 + NO2), and sulfur dioxide (SO2) were observed on high-O3-and-PM2.5 days. Vehicle emissions were identified as the primary anthropogenic sources of volatile organic compounds (VOCs), contributing the most to VOCs (58.4 ± 1.3%), O3 formation (45.3 ± 0.6%), and PM2.5 formation (46.6 ± 0.4%). Cities in Guangdong Province around Shenzhen were identified as major potential source regions of O3 and PM2.5 during high-O3-and-PM2.5 days. These findings will be valuable in developing simultaneous pollution control strategies for PM2.5 and O3 in Shenzhen.

Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.

BackgroundOn-pump valve surgeries are associated with high morbidity and mortality. The present study aimed to reliably predict a composite outcome of postoperative complications using a minimum of easily accessible clinical parameters.MethodsA total of 7,441 patients who underwent valve surgery were retrospectively analyzed. Data for 6,220 patients at West China Hospital of Sichuan University were used to develop a predictive model, which was validated using data from 1,221 patients at the Second Affiliated Hospital of Zhejiang University School of Medicine. The primary outcome was a composite of major complications: all-cause death in hospital, stroke, myocardial infarction, and severe acute kidney injury. The predictive model was constructed using the least absolute shrinkage and selection operator as well as multivariable logistic regression. The model was assessed in terms of the areas under receiver operating characteristic curves, calibration, and decision curve analysis.ResultsThe primary outcome occurred in 129 patients (2.1%) in the development cohort and 71 (5.8%) in the validation cohort. Six variables were retained in the predictive model: New York Heart Association class, diabetes, glucose, blood urea nitrogen, operation time, and red blood cell transfusion during surgery. The C-statistics were 0.735 (95% CI, 0.686–0.784) in the development cohort and 0.761 (95% CI, 0.694–0.828) in the validation cohort. For both cohorts, calibration plots showed good agreement between predicted and actual observations, and ecision curve analysis showed clinical usefulness. In contrast, the well-established SinoSCORE did not accurately predict the primary outcome in either cohort.ConclusionsThis predictive nomogram based on six easily accessible variables may serve as an “early warning” system to identify patients at high risk of major complications after valve surgery.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT04476134].

BackgroundMetabolic disorders caused by intestinal microbial dysregulation are considered to be important causes of gestational diabetes mellitus (GDM). Increasing evidence suggests that the diversity and composition of gut microbes are altered in disease states, yet the critical microbes and mechanisms of disease regulation remain unidentified.MethodsPubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), the Web of Science™ (Clarivate™, Philadelphia, PA, USA), and the Cochrane Library databases were searched to identify articles published between 7 July 2012 and 7 July 2022 reporting on case–control and controlled studies that analyzed differences in enterobacteria between patients with GDM and healthy individuals. Information on the relative abundance of enterobacteria was collected for comparative diversity comparison, and enterobacterial differences were analyzed using random effects to calculate standardized mean differences at a p-value of 5%.ResultsA total of 22 studies were included in this review, involving a total of 965 GDM patients and 1,508 healthy control participants. Alpha diversity did not differ between the participant groups, but beta diversity was significantly different. Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the dominant bacteria, but there was no significant difference between the two groups. Qualitative analysis showed differences between the groups in the Firmicutes/Bacteroidetes ratio, Blautia, and Collinsella, but these differences were not statistically different.ConclusionEnterobacterial profiles were significantly different between the GDM and non-GDM populations. Alpha diversity in patients with GDM is similar to that in healthy people, but beta diversity is significantly different. Firmicutes/Bacteroidetes ratios were significantly increased in GDM, and this, as well as changes in the abundance of species of Blautia and Collinsella, may be responsible for changes in microbiota diversity. Although the results of our meta-analysis are encouraging, more well-conducted studies are needed to clarify the role of the gut microbiome in GDM. The systematic review was registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) as CRD42022357391.

Anemia often occurs in patients undergoing cardiac surgery, which increases the incidence and related risks of blood transfusion together with surgical bleeding.Both anemia and transfusion were associated with poor prognosis and increased mortality.Current practice guidelines generally recommend the implementation of patient blood management (PBM), which relies on anemia management and restrictive transfusion to reduce perioperative blood loss and transfusion rate, and improve the prognosis of patients.This article reviews recent research progress of anemia management and blood transfusion in adult patients undergoing cardiac surgery, in order to provide basis for the practice of PBM in cardiac surgery patients in the future.

Abstract Background Low-density lipoprotein receptor-related protein 4 (LRP4) plays a critical role in the central nervous system (CNS), including hippocampal synaptic plasticity, maintenance of excitatory synaptic transmission, fear regulation, as well as long-term potentiation (LTP). Results In this study, we found that Lrp4 was highly expressed in layer II of the piriform cortex. Both body weight and brain weight decreased in Lrp4 ECD/ECD mice without TMD (Transmembrane domain) and ICD (intracellular domain) of LRP4. However, in the piriform cortical neurons of Lrp4 ECD/ECD mice, the spine density increased, and the frequency of both mEPSC (miniature excitatory postsynaptic current) and sEPSC (spontaneous excitatory postsynaptic current) was enhanced. Intriguingly, finding food in the buried food-seeking test was prolonged in both Lrp4 ECD/ECD mice and Lrp4 cKO (conditional knockout of Lrp4 in the piriform cortex) mice. Conclusions This study indicated that the full length of LRP4 in the piriform cortex was necessary for maintaining synaptic plasticity and the integrity of olfactory function.

Objective: To quantify the potential benefit of adjuvant chemotherapy (ACT) with respect to survival, and to identify factors for predicting prognoses in early gastric cancer patients. Methods: Patients with pT1 gastric cancer (GC) who underwent radical resection with D2 lymphadenectomy were retrospectively analyzed. Based on lymph node metastasis (LNM) status and treatment regimens, patients were classified into groups, and clinicopathological variables, overall survival (OS), and disease-specific survival (DSS) were compared. Results: Of 1,050 enrolled patients, 151 patients (14.4%) had a positive LNM status. Submucosal invasion, undifferentiated state, tumor size > 2 cm, ulceration, and lymphovascular invasion were independent risk factors for LNM using multivariate analyses. The 5-year OS of all patients was 96.4%. HER2 positive, perineural invasion, and LNM were independent factors for worse survival. Patients with pT1N3 GC had a worse 5-year OS and DSS than pT1N0, pT1N1, and pT1N2 patients (P < 0.001). The 5-year OS and DSS for pT1N1 patients showed no significant difference between ACT and surgery only patients. For pT1N2 patients, the 5-year OS and DSS showed no significant difference between S-1 and Xelox treatments. For pT1N3 patients, 7 (36.8%) received S-1, while 12 (63.2%) received Xelox treatment. Patients receiving Xelox treatment showed a better 5-year OS (75.0% vs. 14.3%) and DSS (81.8% vs. 20.0%) than patients receiving S-1 (P < 0.05). Conclusions: Curative surgery only was adequate for patients with pT1N0 and pT1N1. Xelox showed no survival benefits for pT1N2 patients. Therefore, S-1 is the optimal choice for pT1N2 patients, when considering adverse effects. Xelox is recommended for pT1N3 patients.

Background/purpose: The bond strength and durability of highly translucent zirconia ceramics to dentin is still unclear. The purpose of this study was to investigate the effect of various surface treatments on the bond strength of self-adhesive resin cements to high-translucent zirconia crowns and dentin. Materials and methods: A high-transparent zirconia and three self-adhesive resin cements (G-CEM LinkAce (GCL), RelyX U200 (RXU) and TotalCem (TTC)) were used. The zirconia surface was sandblasted with 50 μm alumina particles or coated with an SR Link primer, while a dentin primer (Tetric N-Bond Universal, TBU) was applied to the surface of the dentin. By using three self-adhesive resin cements, zirconia samples were bonded to the dentin surfaces of human teeth. The shear strength of the specimens was measured before and after 10,000-cycle thermocycling or 90-day aging. Results: When using GCL to bond with the untreated dentin and various zirconia surfaces, the shear bond strength of the sandblasted (ZSB) and RS Link primer-coated (ZLK) groups was significantly higher than that of the untreated control group (Zc). However, in the case of TBU-treated dentin, the shear strength of the ZSB + LK + DTBU group was significantly higher than that of the other groups. After thermocycling and aging, the shear strength of the ZSB + LK + DTBU group using GCL and RXU cements decreased slightly, while the TTC showed no impact. Conclusion: The zirconia surface pretreated by sandblasting and bonding agent, which was sequentially bonded with a primer-treated dentin by using resin cements, can provide excellent shear bond strength and anti-aging performance.