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Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. Methods and design The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. Conclusions As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. Registration Number in ClinicalTrials.gov NCT05311072.

Background and AimAmmoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor, holds promise for major depressive disorder treatment. This study aimed to thoroughly investigate its preclinical drug metabolism and pharmacokinetics (DMPK) profiles.MethodsThe preclinical DMPK profiles of ammoxetine were examined through in vitro, in vivo, and in silico methods.ResultsAssessment of blood-brain barrier penetration via MDCK-MDR1 cells revealed strong brain permeation by ammoxetine, despite being a probable P-glycoprotein (P-gp) substrate. Molecular docking indicated a robust binding interaction between ammoxetine and P-gp. Ammoxetine was well absorbed orally, with Tmax ranging from 0.75 to 3.83 h in rats and 0.75–1.40 h in beagle dogs. At a 2 mg/kg dose in beagle dogs, ammoxetine exhibited an absolute bioavailability of approximately 42%. Plasma protein binding rates were around 50%–60% in beagle dogs, rats, and humans, suggesting moderate binding. Tissue distribution studies displayed rapid and extensive ammoxetine spread in major rat tissues post-gavage, with notable brain exposure and no tissue accumulation. Cumulative excretion rates in rats’ urine, feces, and bile accounted for only 1.11% of the total administered drug, indicating extensive transformation into metabolites. Chiral inversion of ammoxetine was absent in vivo. Metabolic stability varied across species using liver microsomes, but beagle dogs showed clearance rates more akin to humans. Metabolic pathways unveiled two key metabolites, M1 and M2. M1, likely generated through methylenedioxyphenyl ring oxidation, involves CYP2C19 and CYP3A4, crucial human cytochrome P450 (CYP) enzymes for liver metabolism, while M2 is M1’s glucuronide conjugate. Ammoxetine may exhibit saturation elimination trends with increasing doses in rats and beagle dogs. A high-throughput assay using the cocktail-substrate method indicated weak CYP inhibition by ammoxetine on CYP2D6 and CYP1A2, with minimal effects on other CYP enzymes, suggesting a low likelihood of CYP inhibition-related drug-drug interactions.ConclusionThis study presents encouraging DMPK profiles of ammoxetine, backing its potential as a candidate compound for future clinical assessments.

Sodium Danshensu (SDSS) is extracted from Salvia miltiorrhiza and has many pharmacological effects. However, little is known about its effects on muscle fiber formation and metabolism. Here, we aimed to investigated the role and molecular mechanisms of SDSS in modulating the formation of skeletal muscle fiber. C2C12 cells were incubated in differentiation medium with or without SDSS for 4 days. C57BL/6 mice were orally administered SDSS by gavage once a day for 8 weeks. Grip strength, treadmill, muscle weight, western blotting, qPCR, immunofluorescence staining and H&E staining were performed. SDSS target proteins were searched through drug affinity responsive target stability (DARTS) and mass spectrometry analysis. Furthermore, molecular docking was carried out for Pyruvate kinase M1 (PKM1). The effect of PKM1 on myosin heavy chain (MyHCs) gene expression was verified by knockdown of PKM1 experiment. SDSS induced oxidative muscle fiber-related gene expression, and inhibited glycolytic fiber-related gene expression in C2C12 cells. Muscle mass, the percentage of slow oxidative fibers, succinic dehydrogenase activity, muscle endurance, glucose tolerance, and the expression of the MyHC1 and MyHC2a genes increased while MyHC2b expression, lactate dehydrogenase activity, and the percentage of glycolytic muscle fibers decreased in SDSS-treated mice. Mechanistically, SDSS bound to the pyruvate kinase PKM1 and significantly repressed its activity. PKM1 inhibited MyHC1 and MyHC2a expression but promoted MyHC2b expression. SDSS also significantly attenuated the effects of PKM1 on muscle fiber-related gene expression in C2C12 cells. Our findings indicate that SDSS promotes muscle fiber transformation from the glycolytic type to the oxidative type by inhibiting PKM1 activity, which provide a new idea for treating muscle atrophy, muscle metabolism diseases and improving animal meat production.

Abstract Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

Abstract Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats.

Abstract Objective It has been demonstrated that IDO1, a target of immune checkpoint inhibition, functions as an oncogene in the majority of human malignancies. IDO1’s function in human pan-cancers hasn’t been thoroughly studied, though. Materials and methods The Kaplan–Meier (K-M) and COX analyses were applied to the survival analysis. Furthermore, we used Spearman’s correlation analysis to examine the associations between IDO1 and microsatellite instability (MSI), DNA methyltransferases (DNMTs), tumor mutational burden (TMB), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers. Moreover, immunohistochemical analysis and qRT-PCR were used to evaluate IDO1’s expression in pan-cancer cells. Results The findings of this study reveal that IDO1 has abnormal expression in a number of malignancies and is related to the prognosis for UVM, LGG, KIRP, GBM, LAML, OV, READ, MESO, SARC, SKCM, and HNSC. Furthermore, the aberrant IDO1 expression was connected to the TMB, MSI, MMR, drug sensitivity, immune cells infiltrating, and tumor immune microenvironment across a variety of cancer types. The PCR results showed that in contrast to normal cells, IDO1 was found to be significantly highly expressed in breast cancer cells and hepatocellular carcinoma cells, and significantly lowly expressed in gastric cancer cells. Conclusion The clinical treatment of IDO1 is now better supported by a theoretical basis and guidelines provided by our study.

Abstract Background Clinical characteristics of patients with pulmonary thromboembolism have been described in previous studies. Although very old patients with pulmonary thromboembolism are a special group based on comorbidities and age, they do not receive special attention. Objective This study aims to explore the clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism in a relatively large population. Design and participants The study included a total of 7438 patients from a national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES). Consecutive patients with acute pulmonary thromboembolism were enrolled and were divided into three groups. Comparisons were performed between these three groups in terms of clinical characteristics, comorbidities and in-hospital prognosis. Mortality predictors were analyzed in very old patients with pulmonary embolism. Key results In 7,438 patients with acute pulmonary thromboembolism, 609 patients aged equal to or greater than 80 years (male 354 (58.1%)). There were 2743 patients aged between 65 and 79 years (male 1313 (48%)) and 4095 patients aged younger than 65 years (male 2272 (55.5%)). Patients with advanced age had significantly more comorbidities and worse condition, however, some predisposing factors were more obvious in younger patients with pulmonary thromboembolism. PaO2

Abstract High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.

Highlights Oxygen-coordinated single-atom Mn catalyst was fabricated via introducing oxygen functional groups rich bacterial cellulose as the adsorption regulator through a combined impregnation–pyrolysis–etching synthetic route. Mn–O–C as the electrocatalyst exhibits superior electrocatalytic activity toward ammonia synthesis with a maximum NH3 yield rate of 1476.9 ± 62.6 μg h −1 cm −2 at − 0.7 V (vs. RHE) and a faradaic efficiency of 89.0 ± 3.8% at − 0.5 V (vs. RHE) under ambient conditions. Electrocatalytic mechanism of Mn–(O–C2)4 site for nitrate reduction reaction is unveiled by a combination of in situ spectroscopy characterization and computational study.

Abstract Continuous passive motion (CPM) is an adjunct therapy to the standard postoperative rehabilitation regimen of joint injuries. The capability of real-time monitoring actual bending angle of knee joints is highly desired for treatment strategies of personalized postoperative rehabilitation and telemedicine. Here we report an intelligent CPM system for personalized rehabilitation and telemedicine based on the flexible and versatile ionotronic that possesses impressive mechanical properties (2.56 MPa tensile strength; 11.63 MJ m−3 toughness), fast self-recovery ability (60 s) and broaden environmental tolerance (−60–45 °C). Especially, the ionotronic responds fast and shows stability for cyclic strain sensing, ensuring the detection of actual joint bending angle with high sensitivity and reliability. The intelligent CPM system assembled with this ionotronic and a wireless transmitter was constructed, opening up a horizon for developing digital intelligent medical that can remotely monitor the movement of hospitalized/at-home patients who use CPM for personalized postoperative rehabilitation.

To better understand how global and regional-scale climate has changed, high-resolution records for environmental changes are still needed in southwestern (SW) China during the Late Holocene epoch. This study presents a well-dated high-resolution diatom analysis from a 1.66-m-long sediment core taken from Lake Cuogeda (CGD) on the southeast (SE) edge of the Tibetan Plateau to document environmental changes over the past ∼4000 years. Diatom and other geochemical proxies show that, from 3850 to 3430 cal yr BP (before present, 0 BP=1950 AD, 1900 to 1480 BC), the environment of Lake CGD is acidic, oligotrophic, and enriched with humic acids. And the lake ice cover duration is short during this period. During 3430–1550 cal yr BP (1480 BC-400 AD), Lake CGD has less humic acid and a relatively high pH environment. The ice cover duration is longer, and the temperature drops during this period. Our multi-indicator recorded two environment fluctuations at ∼2800 cal yr BP (850 BC) and 2210–1950 cal yr BP (260 BC-0 AD). From 1550 to 3.6 cal yr BP (400–1946 AD), the lake ecosystem changed to a higher pH condition and had a prolonged freezing time. From 3.6 cal yr BP (1946 AD) to the present, Lake CGD’s water was acidic, with an environment of shorter duration of ice cover and stronger lake water turbulence. Comparisons between the CGD records and other climate reconstructions underscore the relevance of the CGD record for regional and global environments. Comparisons indicate that the environment evolution pattern of SW China during the Late Holocene was greatly affected by solar radiation and North Atlantic sea surface temperature.

Summary: Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p

Abstract Background A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. Methods We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. Results After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10−14), ABO rs582094 (p-value = 1.16 × 10−10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10−17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. Conclusions We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

PurposeThe relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs.MethodsIn this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann–Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility.ResultsPCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p

Abstract Background Glomerular damage is a common clinical indicator of nephrotic syndrome. High-dose hormone treatment often leads to hormone resistance in patients. How to avoid resistance and improve the efficiency of hormone therapy draws much attention to clinicians. Methods Adriamycin (ADR) was used to induce nephropathy model in SD rats. The rats were treated with dexamethasone (DEX), icariin (ICA), and DEX + ICA combination therapy. The changes in urinary protein (UP), urea nitrogen (BUN), and serum creatinine (SCR) contents in rats were detected by enzyme-linked immunosorbent assay (ELISA), and the degree of pathological injury and the expression level of podocin were detected by HE staining and immunohistochemistry, to test the success of the model and the therapeutic effects of three different ways. The effect of treatments on podocytes autophagy was evaluated via transfection of mRFP-GFP-LC3 tandem adenovirus in vitro. Results The contents of UP, SCR, and BUN were significantly increased, the glomerulus was seriously damaged, and the expression of Nephrosis2 (NPHS2) was significantly decreased in the ADR-induced nephrotic syndrome rat model compared to that of the control group. DEX, ICA, and the DEX + ICA combined treatment significantly alleviated these above changes induced by ADR. The combined treatment of DEX + ICA exhibited better outcome than single treatment. The combined treatment also restored the podocyte autophagy, increased the expression of microtubule-associated protein light-chain 3II (LC3II), and reduced the expression of p62 in vitro. The combined treatment protects podocytes by mediating the PI3K/AKT/mTOR (rapamycin complex) signaling pathway. Conclusion ICA enhances the therapeutic effect of DEX on the nephrotic syndrome.

Objective The present study identified novel renal tubular biomarkers that may influence the diagnosis and treatment of focal segmental glomerulosclerosis (FSGS) based on immune infiltration.Methods Three FSGS microarray datasets, GSE108112, GSE133288 and GSE121211, were downloaded from the Gene Expression Omnibus (GEO) database. The R statistical software limma package and the combat function of the sva package were applied for preprocessing and to remove the batch effects. Differentially expressed genes (DEGs) between 120 FSGS and 15 control samples were identified with the limma package. Disease Ontology (DO) pathway enrichment analysis was conducted with statistical R software to search for related diseases. Gene set enrichment analysis (GSEA) was used to interpret the gene expression data and it revealed many common biological pathways. A protein-protein interaction (PPI) network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and hub genes were identified by the Cytoscape (version 3.7.2) plug-in CytoHubba. The plug-in Molecular Complex Detection (MCODE) was used to screen hub modules of the PPI network in Cytoscape, while functional analysis of the hub genes and hub nodes involved in the submodule was performed by ClusterProfiler. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) analysis were used to screen characteristic genes and build a logistic regression model. Receiver operating characteristic (ROC) curve analyses were used to investigate the logistic regression model and it was then validated by an external dataset GSE125779, which contained 8 FSGS samples and 8 healthy subjects. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to calculate the immune infiltration of FSGS samples.Results We acquired 179 DEGs, 79 genes with downregulated expression (44.1%) and 100 genes with upregulated expression (55.9%), in the FSGS samples. The DEGs were significantly associated with arteriosclerosis, kidney disease and arteriosclerotic cardiovascular disease. GSEA revealed that these gene sets were significantly enriched in allograft rejection signaling pathways and activation of immune response in biological processes. Fifteen genes were demonstrated to be hub genes by PPI, and three submodules were screened by MCODE linked with FSGS. Analysis by machine learning methodologies identified nuclear receptor subfamily 4 group A member 1 (NR4A1) and dual specificity phosphatase 1 (DUSP1) as sensitive tubular renal biomarkers in the diagnosis of FSGS, and they were selected as hub genes, as well as hub nodes which were enriched in the MAPK signaling pathway. Immune cell infiltration analysis revealed that the genetic biomarkers were both correlated with activated mast cells, which may amplify FSGS biological processes.Conclusion DUSP1 and NR4A1 were identified as sensitive potential biomarkers in the diagnosis of FSGS. Activated mast cells have a decisive effect on the occurrence and development of FSGS through tubular lesions and tubulointerstitial inflammation, and they are expected to become therapeutic targets in FSGS.

Genome-wide analyses of maize populations have clarified the genetic basis of crop domestication and improvement. However, limited information is available on how breeding improvement reshaped the genome in the process of the formation of heterotic groups. In this study, we identified a new heterotic group (X group) based on an examination of 512 Chinese maize inbred lines. The X group was clearly distinct from the other non-H&L groups, implying that X × HIL is a new heterotic pattern. We selected the core inbred lines for an analysis of yield-related traits. Almost all yield-related traits were better in the X lines than those in the parental lines, indicating that the primary genetic improvement in the X group during breeding was yield-related traits. We generated whole-genome sequences of these lines with an average coverage of 17.35× to explore genome changes further. We analyzed the identity-by-descent (IBD) segments transferred from the two parents to the X lines and identified 29 and 28 IBD conserved regions (ICRs) from the parents PH4CV and PH6WC, respectively, accounting for 28.8% and 12.8% of the genome. We also identified 103, 89, and 131 selective sweeps (SSWs) using methods that involved the π, Tajima’s D, and CLR values, respectively. Notably, 96.13% of the ICRs co-localized with SSWs, indicating that SSW signals concentrated in ICRs. We identified 171 annotated genes associated with yield-related traits in maize both in ICRs and SSWs. To identify the genetic factors associated with yield improvement, we conducted QTL mapping for 240 lines from a DH population (PH4CV × PH6WC, which are the parents of X1132X) for ten key yield-related traits and identified a total of 55 QTLs. Furthermore, we detected three QTL clusters both in ICRs and SSWs. Based on the genetic evidence, we finally identified three key genes contributing to yield improvement in breeding the X group. These findings reveal key loci and genes targeted during pedigree breeding and provide new insights for future genomic breeding.

The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2–5) named albaphenol A–E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7–16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1–16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 μM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5–32.8 μM) than the positive control galantamine (IC50 35.3 μM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 μM. The structure–activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor–enzyme complex.

Abstract We intended to evaluate the diagnosis and treatment status of pulmonary hypertension (PH) in China and provide the basis for the design of the Chinese PH centers system. A questionnaire survey was conducted by sampling from Chinese Class A tertiary hospitals that have carried out the clinical work of PH, including the composition of PH clinical team, the current application of examinations related to PH diagnosis, the availability of PAH‐specific medicine and the implementation of PH‐related intervention and surgery. A total of 44 valid questionnaires from 20 provinces were collected in this survey. In the vast majority of centers (83.33%, n = 35), pulmonary artery catheterization was routinely performed under X‐ray guidance. In 19.05% (n = 8) of centers, pressure measurements were determined at the right time (the end of normal expiration). Only 73.81% (n = 31) centers have carried out acute vasoreactivity testing. Prostacyclin analogues and prostaglandin receptor agonists were just prescribed in 45.45% (n = 20) of the centers. 19 centers (43.18%) were capable of performing balloon pulmonary angioplasty (BPA) and pulmonary endarterectomy (PEA), while 25% (n = 11) were able to perform BPA, PEA, and lung transplantation. There was no significant difference in the diagnosis and treatment of PH between economic regions. The majority of Chinese tertiary hospitals were well equipped with the corresponding personnel, examinations and medicines related to PH, but the standardization and specialization of the management of PH need to be strengthened.

Abstract Background Renal function is associated with prognoses for acute pulmonary embolism (PE). Objective To investigate the application of anticoagulants and dosage of LMWH among patients with renal insufficiency (RI), and the association between LWMH dosage and the patients’ in-hospital outcomes. Methods Adult patients diagnosed with non-high risk acute PE from 2009 to 2015, with available data of creatinine clearance (CCr) were enrolled from a multicenter registry in China. Renal insufficiency (RI) was defined as CCr 100 IU/kg/day). All-cause death, PE-related death and bleeding events during hospitalization were analyzed as endpoints. Results Among the enrolled 5870 patients, RI occurred in 1311 (22.3%). 30 ≤ CCr

Apiospora, an ascomycetous genus in Apiosporaceae, comprises saprobes, endophytes, and pathogens of humans and plants. They have a cosmopolitan distribution with a wide range of hosts reported from Asia. In the present study, we collected and isolated Apiospora species from Wurfbainia villosa and grasses in Guangdong and Yunnan provinces in China. Multi-locus phylogeny based on the internal transcribed spacer, the large subunit nuclear rDNA, the partial translation elongation factor 1-α, and β-tubulin was performed to clarify the phylogenetic affinities of the Apiospora species. Based on the distinctive morphological characteristics and molecular evidence, Ap. endophytica, Ap. guangdongensis, Ap. wurfbainiae, and Ap. yunnanensis are proposed. Descriptions, illustrations, and notes for the newly discovered species are provided and compared with closely related Apiospora species. An updated phylogeny of Apiospora is presented, along with a discussion on the phylogenetic affinities of ambiguous taxa.

Vegetation on the Southwestern Tibetan Plateau (SWTP) is critical to ensuring ecological security and promoting regional economic and social development. Here, we explored the relationship between topographic factors (elevation, slope, and aspect) and the spatial patterns in the normalized difference vegetation index (NDVI) in the SWTP over the past 20 years. The results found that the NDVI in the SWTP was primarily influenced by elevation and slope. The regions with significant variations in NDVI were concentrated between 4500 m to 5500 m and slopes ranging from 0° to 15°. Although the influence of aspect on NDVI was small, there was a decreasing trend in NDVI on sunny slopes and an increasing trend on shady slopes. Dominant topographic conditions were identified by considering 230 different combinations of elevation, slope, and aspect. The combination of topographic parameters indicated stronger patterns in NDVI variability, notably within sections of 0°–25°slopes and below 5000 m elevation. These findings highlight the relevance of topography, notably slope and aspect, for vegetation in alpine settings. The information gathered from this study about the prevailing topographic distribution and vegetation growth state in the SWTP can help with future ecological restoration and conservation efforts in the Tibetan Plateau and other comparable regions worldwide.

Genic male sterility (GMS) is one of the most important resources for exploiting heterosis in crop breeding, so that identifying genomic loci regulating GMS is desirable. However, many regulatory genes controlling GMS have not yet been characterized in maize, owing partly to a lack of genetic materials. We generated a recessive male-sterile maize mutant in the Jing 724 genetic background via ethyl methanesulfonate treatment, and found the male sterility to be due to a single gene mutation. Bulk-segregant RNA sequencing of three replicates indicated that one genomic region located at the end of chromosome 4 was associated with the observed mutant phenotype. Among genes with nonsynonymous mutations, Zm00001d053895 (bHLH51) showed abolished expression in the sterile bulks and was annotated as a bHLH transcription factor orthologous to Arabidopsis AMS, suggesting an association with the male sterility of the mutant. Kompetitive Allele-Specific PCR assays further validated the exclusive correlation of male sterility with the single C-to-T mutation in the fifth exon. The new maize mutant and the potential SNP locus provide novel genetic material for investigating the molecular mechanism underlying tapetal development and may facilitate the improvement of hybrid production systems.

Two undescribed butenolide derivatives, asperteretal J (1) and K (2), together with 13 known ones (3–15) were isolated from an endophytic fungus Aspergillus terreus SGP-1, the fermentation product of which exhibited selective inhibitory activity toward butyrylcholinesterase. The structures of the new compounds were elucidated based on HRMS and NMR data, and the absolute configurations were determined by specific optical rotation comparison. All compounds were evaluated for cholinesterase inhibitory effects with galantamine as a positive control. Compounds 4–8 selectively inhibited butyrylcholinesterase with IC50 values of 18.4–45.8 µM in a competitive manner, with Ki values of 12.3–38.2 µM. The structure-activity relationship was discussed. Molecular docking and dynamic simulation of the inhibitor-enzyme complex were performed to better understand the interactions.

Abstract Direct electrocatalytic oxidation of benzene has been regarded as a promising approach for achieving high‐value phenol product, but remaining a huge challenge. Here an oxygen‐coordinated nickel single‐atom catalyst (Ni–O–C) is reported with bifunctional electrocatalytic activities toward the two‐electron oxygen reduction reaction (2e− ORR) to H2O2 and H2O2‐assisted benzene oxidation to phenol. The Ni–(O–C2)4 sites in Ni–O–C ar proven to be the catalytic active centers for bifunctional 2e− ORR and H2O2‐assisted benzene oxidation processes. As a result, Ni–O–C can afford a benzene conversion as high as 96.4 ± 3.6% with a phenol selectivity of 100% and a Faradaic efficiency (FE) of 80.2 ± 3.2% with the help of H2O2 in 0.1 m KOH electrolyte at 1.5 V (vs RHE). A proof of concept experiment with Ni–O–C concurrently as cathode and anode in a single electrochemical cell demonstrates a benzene conversion of 33.4 ± 2.2% with a phenol selectivity of 100% and a FE of 44.8 ± 3.0% at 10 mA cm−2.

Abstract Clausena lansium (Lour.) Skeels seeds have been shown to have diverse beneficial medical value due to their unique active components. This study analysed the composition of essential oils (EOs) of C. lansium seeds and investigated their potential antifungal effects against Candida strains. A total of forty-six components were identified in all samples by gas chromatography-mass spectrometry (GC–MS). The main components were sabinene, β-phellandrene and 4-terpineol. Thirteen EOs of C. lansium seeds were classified into three clusters based on their components. Cluster analysis showed that the difference between the tropics and subtropics was the greatest. These EOs and the three main chemicals showed different antifungal activities against five Candida species (C. albicans, C. tropicalis, C. glabrata, C. krusei and C. parapsilosis). The antifungal activity against C. glabrata and C. krusei was higher than that against other Candida strains. EOs of C. lansium seeds displayed noteworthy antifungal activity against both sensitive and fluconazole-resistant strains, with inhibition zone diameters in the range of 9.4–23.4 mm. Comprehensive analysis illustrated the importance of sabinene, β-phellandrene and 4-terpineol to antifungal activity, and there may be some synergistic effects with other components. These results represent the first report about the correlation between the chemical composition of EOs of C. lansium seeds and antifungal activity. Taken together, the results obtained provide scientific evidence for the traditional use of C. lansium seeds waste.

Abstract The ever‐growing depletion of precious metals in modern electronic industry necessitates unremitting exploitation of novel materials for gold recovery from e‐waste. Herein, a freestanding poly(imine dioxime) (PIDO) membrane has been successfully fabricated for highly efficient recovery of gold from e‐waste. The consummate integration of abundant binding sites and hierarchically porous architecture renders the resulting PIDO membrane with a record‐breaking uptake capacity (9250 mg g−1) toward gold, fast adsorption equilibrium time, as well as satisfactory regeneration and reusability. Furthermore, PIDO membrane is also well competent for selective gold recovery from waste central processing unit leachate with remarkable efficiency (>99%). Considering high recovery efficiency, outstanding selectivity, and simple/scalable production process, the proposed PIDO membrane will hold huge prospect in the sustainable recovery of gold from e‐waste.

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) patients may present with atherosclerotic lesions in their pulmonary arteries, but their clinical characteristics remain unclear. The metabolic pathways associated with the atherosclerotic lesions may explain their occurrence and have implications for interventions, but they have not been investigated.MethodsWe collected pulmonary endarterectomy (PEA) samples of CTEPH patients from December 2016 to August 2021. Following a detailed pathological examination of the PEA specimen, the patients were divided into those with and without lesions, and age- and sex matching were performed subsequently using propensity score matching (n = 25 each). Metabolomic profiling was used to investigate the metabolites of the proximal lesions in the PEA specimens.ResultsIn our study population, 27.2% of all PEA specimens were found to contain atherosclerotic lesions. CTEPH patients with atherosclerotic lesions were more likely to have a history of symptomatic embolism and had a longer timespan between embolism and surgery, whereas the classic risk factors of systemic and coronary circulation could not distinguish CTEPH patients with or without atherosclerotic lesions. Metabolomic profiling revealed that the formation of atherosclerotic lesions in CTEPH was closely related to altered glycine, serine, and threonine metabolic axes, possibly involved in cellular senescence, energy metabolism, and a proinflammatory microenvironment.ConclusionThe occurrence of atherosclerotic lesions in the pulmonary arteries of CTEPH was associated with symptomatic thromboembolic history and prolonged disease duration. The results revealed a new link between atherosclerotic lesions and aberrant amino acid metabolism in the context of CTEPH for the first time. This study has characterized the clinical and metabolic profiles of this distinct group of CTEPH patients, providing new insights into disease pathogenesis and potential interventions.

This case report describes a 58-year-old, never-smoking housewife with chief complaints of progressively worsening cough, dyspnea, and intermittent fever, who was initially misdiagnosed with community-acquired pneumonia (CAP). However, her pulse oximetry oxygen saturation continued to decline, and eventually, she underwent an endotracheal intubation. Fortunately, transbronchial cryobiopsy (TBCB) assisted by extracorporeal membrane oxygenation (ECMO) was performed in the most critical situation, and it revealed an organizing pneumonia (OP) pattern. OP describes a histological pattern of acute or subacute pulmonary damage, which may be idiopathic or associated with a known or unknown underlying disease. A definitive diagnosis of OP usually obtained from pathology, and surgical lung biopsy with large lung tissue is recommended. However, since the surgical lung biopsy was not convenient for this patient after mechanical ventilation, bedside TBCB supported by ECMO was selected. To our knowledge, we are the first to report the pathological diagnosis of ECMO assisted TBCB in acute respiratory failure. When oxygenation cannot be maintained after endotracheal intubation and surgical lung biopsy is not feasible, ECMO-supported TBCB may be a good choice to obtain lung tissue for histopathological diagnosis in patients with acute lung injury of unknown etiology.

Aglaonema modestum (A. modestum) (Araceae) is an evergreen herbage, which is intensively grown as an ornamental plant in South China. A new disease was observed in A. modestum from 2020 to 2021 in Guangdong province, China. The disease symptoms associated with plants were initial leaf wilt, stem rot, and resulting plant death, leading to severe economic losses. In total, six Fusarium isolates were obtained from diseased plants. The putative pathogen was identified using both morphological characteristics and molecular phylogenetic analysis of calmodulin A (cmdA), RNA polymerase largest subunit 1 (rpb1), RNA polymerase II (rpb2), translation elongation factor-1α (tef1-α), and beta-tubulin (β-tubulin) sequences. Two Fusarium species were identified, namely, one new species, Fusarium aglaonematis (F. aglaonematis) belonging to Fusarium fujikuroi species complex. In addition, Fusarium elaeidis (F. elaeidis) belonging to the Fusarium oxysporum (F. oxysporum) species complex was also identified. Pathogenicity assays were conducted by inoculating each species into potted A. modestum plants and co-inoculating two species. The results showed that two Fusarium species could infect plants independently and can infect them together. Co-infection of these two species enhanced the disease severity of A. modestum. Compared to single inoculation of F. elaeidis, severity was higher and disease development was quicker when plants were only inoculated with F. aglaonematis. In addition, these two Fusarium species could infect Aglaonema plants without wounds, while inoculation with a physical injury increased disease severity. This is the first report of co-infection by F. aglaonematis and F. elaeidis causing stem rot on A. modestum worldwide. This study will be an addition to the knowledge of Fusarium diseases in ornamental plants. These results will provide a baseline to identify and control diseases associated with A. modestum.

To assess the impact of the relative displacement between machines and subjects, the machine angle and the fine-tuning of the subject posture on the segmentation accuracy of chest X-rays, this paper proposes a Position and Direction Network (PDNet) for chest X-rays with different angles and positions that provides more comprehensive information for cardiac image diagnosis and guided surgery. The implementation of PDnet was as follows: First, the extended database image was sent to a traditional segmentation network for training to prove that the network does not have linear invariant characteristics. Then, we evaluated the performance of the mask in the middle layers of the network and added a weight mask that identifies the position and direction of the object in the middle layer, thus improving the accuracy of segmenting targets at different positions and angles. Finally, the active-shape model (ASM) was used to postprocess the network segmentation results, allowing the model to be effectively applied to 2014 × 2014 or higher definition chest X-rays. The experimental comparison of LinkNet, ResNet, U-Net, and DeepLap networks before and after the improvement shows that its segmentation accuracy (MIoU) are 5%, 6%, 20%, and 13% better. Their differences of losses are 11.24%, 21.96%, 18.53%, and 13.43% and F-scores also show the improved networks are more stable.

KPNA7 is an essential nuclear protein for early embryogenesis and normal fertility. The aim of our study was to determine the associations between single nucleotide polymorphisms (SNPs) in the KPNA7 gene and the reproductive traits in France Large White pigs. Six new SNPs were identified by sequencing. Sows with CT genotype of rs81308652 had a significantly higher total number born than sows with CC and TT genotype in first parity. Litters from sows with TT genotype of rs81308652 had a significantly lower number of weak births than litters from sows with CC and CT genotype in multi parity. Individuals with GG genotype of rs327848277 showed higher litter weight at birth (LWB) and number of healthy births than individuals with genotype GT and TT in first parity, and individuals with genotype GG had lower LWB compared to other genotypes in multi parity. However, we obtained no statistically significant results for association between the SNPs in other four loci and reproductive traits in both primiparous and multiparous pigs. In conclusion, our results show that there are significant association of identified SNPs located in KPNA7 gene with pig reproductive traits, and provided a theoretical basis for genetic improvement of pig reproductive traits.

Despite much attention on the history of goat evolution, information on origin, demographic history, and expansion route remains controversial. To address these questions, we collected 4,189 published goat DNA sequences including 1,228 sequences from 57 breeds in China and 2,961 sequences including 193 goat breeds from 71 other countries and carried out an integrated analysis. We found goat breeds from South China had the highest genetic diversity of lineage B, and subclades B2 only were found in Southwest China, suggesting that lineage B (particularly, subclade B2) probably originated from Southwest China and its surrounding areas. In addition, in this study, we found that lineage A from South China also presented higher genetic diversity and earlier expansion time (10, 606 years ago), even earlier than breeds from the Middle East. Hence, we speculated that South China and surrounding areas were the origin of lineage B and also the transportation hub for lineage A spreading to North China and Southwest Asia. Furthermore, according to the analysis of correlation between genetic differentiation value λ1 and λ2 and geographical distance, we further confirmed two phases of migration in goat breeds of North China. These results will contribute to a better understanding of the origin and migration history of domestic goat.

ObjectiveTo assess the efficacy and safety of tenecteplase in patients with pulmonary embolism (PE).MethodsWe completed the literature search on May 31, 2021 using PubMed, EMBASE and the Web of Science. Analyses were conducted according to PE risk stratification, study design and duration of follow-up. The pooled risk ratios (RRs) and its 95% confident intervals (CIs) for death and major bleeding were calculated using a random-effect model.ResultsA total of six studies, with four randomized controlled trials (RCTs) and two cohort studies, were included in this study out of the 160 studies retrieved. For patients with high-risk PE, tenecteplase increased 30-day survival rate (16% vs 6%; P = 0.005) and did not increase the incidence of bleeding (6% vs 5%; P = 0.73). For patients with intermediate-risk PE, four RCTs suggested that tenecteplase reduced right ventricular insufficiency at 24h early in the onset and the incidence of hemodynamic failure without affecting mortality in a short/long-term [

Abstract Background Prostate cancer (PC) is common male cancer with high mortality worldwide. Emerging evidence demonstrated that long noncoding RNAs (lncRNAs) play critical roles in various type of cancers including PC by serving as competing endogenous RNAs (ceRNAs) to modulate microRNAs (miRNAs). LncRNA activated by DNA damage (NORAD) was found to be upregulated in PC cells, while the detailed function and regulatory mechanism of NORAD in PC progression remains largely unclear. Methods Expression of NORAD in PC tissues and cell lines were detected by real-time quantitative PCR (qRT-PCR). NORAD was respectively overexpressed and knocked down by transfection with pcDNA-NORAD and NORAD siRNA into PC-3 and LNCap cells. Cell proliferation, invasion and apoptosis were determined by using CCK-8, Transwell and Flow cytometry assays, respectively. The target correlations between miR-30-5p and NORAD or RAB11A were confirmed by using dual luciferase reporter assay. Moreover, expression levels of RAB11A, the epithelial-mesenchymal transition (EMT) marker proteins and the Wnt pathway related proteins were measured by Western blotting. Tumor xenograft assay was used to study the effect of NORAD on tumor growth in vivo. Results NORAD was upregulated in PC tissues and cells. Overexpression of NORAD promoted cell proliferation, invasion, EMT, and inhibited cell apoptosis; while knockdown of NORAD had the opposite effect. NORAD was found to be functioned as a ceRNA to bind and downregulated miR-30a-5p that was downregulated in PC tumor tissues. Rescue experiments revealed that miR-30a-5p could weaken the NORAD-mediated promoting effects on cell proliferation, invasion and EMT. Furthermore, RAB11A that belongs to a member of RAS oncogene family was verified as a target of miR-30a-5p, and reintroduction of RAB11A attenuated the effects of miR-30a-5p overexpression on cell proliferation, invasion, EMT and apoptosis of PC cells. More importantly, silencing RAB11A partially reversed the promoting effects of NORAD overexpression on cell proliferation, invasion and EMT of PC cells via the WNT/β-catenin pathway. Lastly, tumorigenicity assay in vivo demonstrated that NORAD increased tumor volume and weight via miR-30a-5p /RAB11A pathway. Conclusion Our results indicated a significant role of NORAD in mechanisms associated with PC progression. NORAD promoted cell proliferation, invasion and EMT via the miR-30a-5p/RAB11A/WNT/β-catenin pathway, thus inducing PC tumor growth.

Abstract Background Stalk fracture caused by strong wind can severely reduce yields in maize. Stalks with higher stiffness and flexibility will exhibit stronger lodging resistance. However, stalk flexibility is rarely studied in maize. Stalk fracture of the internode above the ear before tasseling will result in the lack of tassel and pollen, which is devastating for pollination in seed production. In this study, we focused on stalk lodging before tasseling in two maize inbred lines, JING724 and its improved line JING724A1 and their F2:3 population. Results JING724A1 showed a larger stalk fracture angle than JING724, indicating higher flexibility. In addition, compared to JING724, JING724A1 also had longer and thicker stalks, with a conical, frustum-shaped internode above the ear. Microscopy and X-ray microcomputed tomography of the internal stalk architecture revealed that JING724A1 had more vascular bundles and thicker sclerenchyma tissue. Furthermore, total soluble sugar content of JING724A1, especially the glucose component, was substantially higher than in JING724. Using an F2:3 population derived from a JING724 and JING724A1 cross, we performed bulk segregant analysis for stalk fracture angle and detected one QTL located on Chr3: 14.00–19.28 Mb. Through transcriptome data analysis and ∆ (SNP-index), we identified two candidate genes significantly associated with high stalk fracture angle, which encode a RING/U-box superfamily protein (Zm00001d039769) and a MADS-box transcription factor 54 (Zm00001d039913), respectively. Two KASP markers designed from these two candidate genes also showed significant correlations with stalk fracture angle. Conclusions The internode shape and glucose content are possibly correlated with stalk flexibility in maize. Two genes in the detected QTL are potentially associated with stalk fracture angle. These novel phenotypes and associated loci will provide a theoretical foundation for understanding the genetic mechanisms of lodging, and facilitate the selection of maize varieties with improved flexibility and robust lodging resistance.

Organic-inorganic hybrid halide perovskites have been emerged as promising candidates for X-ray detectors while toxicity and instability are known issues. Here, Zhang et al. grow large size lead-free single crystals for high performance X-ray detection and imaging devices that can operate at 100 °C.

ObjectivesThere are conflicting data concerning the prognostic significance of syncope in acute pulmonary embolism (PE). This study aimed to investigate the impact of syncope on clinical outcomes of acute PE, and determine the clinical phenotypes of PE patients with syncope and their correlation with prognosis.MethodsIn the ongoing, national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES) enrolling consecutive patients with acute PE, patients with and without syncope were investigated. Principal component analysis (PCA) was performed using nine variables relevant to syncope and PE, including age, sex, body mass index, history of cardiovascular disease, recent surgery or trauma, malignancy, pulse, systolic blood pressure, and respiratory rate. Patient classification was performed using cluster analysis based on the PCA-transformed data. The clinical presentation, disease severity and outcomes were compared among the phenotypes.ResultsIn 7,438 patients with acute PE, 777 (10.4%) had syncope, with younger age, more females and higher body mass index. Patients with syncope had higher frequency of precordial pain, palpitation, and elevated cardiac biomarkers, as well as higher D-Dimer level. In the syncope group, more patients had right ventricular/left ventricular ratio > 0.9 in ultrasonic cardiogram and these patients had higher estimated pulmonary arterial systolic pressure compared with patients without syncope. As the initial antithrombotic treatment, more patients with syncope received systemic thrombolysis. Despite a higher prevalence of hemodynamic instability (OR 7.626, 95% CI 2.960–19.644, P < 0.001), syncope did not increase in-hospital death. Principal component analysis revealed that four independent components accounted for 60.3% of variance. PE patients with syncope were classified into four phenotypes, in which patients with high pulse and respiratory rate had markedly higher all-cause mortality during admission.ConclusionSyncope was associated with hemodynamic instability and more application of thrombolysis, without increasing in-hospital deaths. Different clinical phenotypes existed in PE patients with syncope, which might be caused by various mechanisms and thus correlated with clinical outcomes.

Cellular senescence is a process that leads to a state of irreversible cell growth arrest induced by a variety of intrinsic and extrinsic stresses. Senescent cells (SnCs) accumulate with age and have been implicated in various age-related diseases in part via expressing the senescence-associated secretory phenotype. Elimination of SnCs has the potential to delay aging, treat age-related diseases and extend healthspan. However, once cells becoming senescent, they are more resistant to apoptotic stimuli. Senolytics can selectively eliminate SnCs by targeting the SnC anti-apoptotic pathways (SCAPs). They have been developed as a novel pharmacological strategy to treat various age-related diseases. However, the heterogeneity of the SnCs indicates that SnCs depend on different proteins or pathways for their survival. Thus, a better understanding of the underlying mechanisms for apoptotic resistance of SnCs will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear SnCs. In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.

Background: Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders, the impact of eryptosis on renal anemia demands attention. However, a systemic analysis concerning the pathophysiology of eryptosis has not been expounded. Summary: The complicated conditions in CKD patients, including oxidative stress, osmotic stress, metabolic stress, accumulation of uremic toxins, and iron deficiency, affects the normal skeleton structure of red blood cells (RBCs) and disturbs ionic homeostasis, causing phosphatidylserine to translocate to the outer lobules of the RBC membrane that leads to early elimination and/or shortening of the red blood cell lifespan (RBCL). Inadequate synthesis of RBCs cannot compensate for their accelerated destruction, thus exacerbating renal anemia. Meanwhile, EPO treatment alone will not reverse renal anemia. A variety of eryptosis inhibitors have so far been found, but evidence of their effectiveness in the treatment of CKD remains to be established. Key Messages: In this review, the pathophysiological processes and factors influencing eryptosis in CKD were elucidated. The aim of this review is to underline the importance of eryptosis in renal anemia and determine some promising research directions or possible therapeutic targets to correct anemia in CKD.

A large number of sinusoidal fractures exist in the open-pit slopes of mines, and the mechanical properties of shear failure are of great significance to the stability of the open-pit slope. Sandstone specimens containing sinusoidal fractures with different undulated heights were prefabricated by the CNC sand-wire-electrode cutting technology to explore the effect of sinusoidal fractures on the mechanical properties of shear failure of rock masses. The TFD-20H/50J rock shear testing machine was used for shear tests on sinusoidal-fracture sandstone with different undulated heights. In the shear loading process, the prefabricated-fracture sandstone specimens with different undulated heights have the fracture-compacting stage, linear-elastic changing stage, bottom-up stage, and residual strength stage. Before peak strength, the sinusoidal prefabricated-fracture rock masses with different undulated heights have the precursory characteristics of decreased stress, which can provide an early warning for the instability and failure of rock masses. The undulated height of sinusoidal fractures significantly affects the fracture initiation and propagation of specimens. Fractures occur and develop from the prefabricated fractures at low undulated height (≤10 mm) to multiple ways under the high undulated height (>10 mm); that is, fractures occur at the prefabricated fractures and the end of specimens simultaneously. With the increased undulated height, the fractures expand from parallel to the slope of the prefabricated fractures to perpendicular to the prefabricated fractures. The fracture propagation direction of sinusoidal-fracture rock masses with different undulated heights is mainly from the middle of the slope surface of prefabricated fractures to the end. It is the main direction of the shear failure of sinusoidal prefabricated fractures, and the monitoring of weak planes should be strengthened in the actual slope engineering.

Stroke is a disease with a high disability rate, having a serious impact on that patient’s working and daily survival quality and bringing economic burden to the family and society. Patients with stroke hemiplegia are mostly tetraplegic and have difficulty regulating their balance, and their long-term symmetry has been destroyed. The application in the rehabilitation process of acupuncture in patients with hemorrhagic stroke may produce unexpected effects. It is very effective to study the effect of acupuncture combined with rehabilitation training on limb movement and patient survival. It is very helpful in improving normal motor function and normal life, increasing joint mobility and muscle strength, and reducing muscle tension. In this paper, it is found that the observational group has a complication rate of 2.13%, in contrast to 17.02% as in the group of control, and the pin-prick combined with a rehabilitative training makes a significant improvement to the patients. This study provides suggestions for the study to investigate acupuncture combined with recovery exercise on limb movement and living capacities of people with stroke paraparesis.

Aim: To summarize the incidence of right heart catheter diagnosed chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) in a meta-analysis.Methods: Cohort studies reporting the incidence of CTEPH after acute PE were identified via search of Medline, Embase, China National Knowledge Infrastructure and WanFang databases.Results: Twenty-two cohort studies with 5,834 acute PE patients were included. Pooled results showed that the overall incidence of CTEPH was 2.82% (95% CI: 2.11–3.53%). Subgroup analyses showed higher incidence of CTEPH in Asians than Europeans (5.08 vs. 1.96%, p = 0.01), in retrospective cohorts than prospective cohorts (4.75 vs. 2.47%, p = 0.02), and in studies with smaller sample size than those with larger sample size (4.57 vs. 1.71%, p < 0.001). Stratified analyses showed previous venous thromboembolic events and unprovoked PE were both significantly associated with increased risk of CTEPH (OR = 2.57 and 2.71, respectively; both p < 0.01).Conclusions: The incidence of CTEPH after acute PE is ~3% and the incidence is higher in Asians than Europeans. Efforts should be made for the early diagnosis and treatment of CTEPH in PE patients, particularly for high-risk population.

Chemical investigation of Aspergillus terreus ASM-1 fermentation resulted in the isolation of three new prenylated aspulvinones V–X (1–3), together with the previously reported analogs, aspulvinone H (4), J-CR (5), and R (6). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, and the absolute configurations of 2 and 3 were determined by ECD comparison. Compounds 1–6 were evaluated for α-glucosidase inhibitory effects with acarbose as positive control. As a result, compounds 1 and 4 exhibited potent α-glucosidase inhibitory activities with IC50 values of 2.2 and 4.6 µM in mixed-type manners. The thermodynamic constants recognized the interaction between inhibitors and α-glucosidase was hydrophobic force-driven spontaneous exothermic reaction. The CD spectra also indicate that the compounds 1 and 4 changed the enzyme conformation. Furthermore, compound 4 significantly suppressed the increases in postprandial blood glucose levels in the C57BL/6J mice.

Background: Lead (Pb) is known to induce detrimental health effects in exposed populations, including hematotoxicity and genotoxicity. Complete blood count (CBC) is a cost-effective and easy way to determine toxicity, and variations in proportion of different types of leukocytes: neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are further evidence of hematotoxicity. However, few studies have been conducted to systematically evaluate effects of occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. Objectives: Our study was aimed to systematically assess the effects of current occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. Methods: Our investigation was performed on 1176 workers from a newly built battery factory in North China. The workers had just entered their current job position in recent years and most of them had no previous history of occupational exposure to Pb. Blood lead levels (BLLs) and leukocytes indices were detected for all participants. Cytokinesis-blocked micronucleus assay (MN; n = 675) and alkaline comet assay (% tail DNA; n = 869) were used to assess genotoxicity. Multivariate linear and Poisson regression analyses were conducted to examine associations between leukocytes indices, genotoxic biomarkers and BLLs with adjustment for covariates. Spearman correlation and mediation analyses were used to investigate relationships between NLR and genotoxicity. Results: Among all the exposed workers, NLR increased with increasing BLLs. However, WBC and LMR did not change significantly. Significant and dose-dependent increases in both MN frequencies and % tail DNA were observed among groups with different exposure doses. Compared with the normal NLR group (1.48 ≤ NLR

Abstract Background Tuberculous meningitis is the most devastating presentation of disease with Mycobacterium tuberculosis. We sought to evaluate treatment outcomes for adult patients with this disease. Methods The Ovid MEDLINE, EMBASE, Cochrane Library and Web of Science databases were searched to identify all relevant studies. We pooled appropriate data to estimate treatment outcomes at the end of treatment and follow-up. Results Among the articles identified, 22 met our inclusion criteria, with 2437 patients. In a pooled analysis, the risk of death was 24.7% (95%CI: 18.7–31.9). The risk of neurological sequelae among survivors was 50.9% (95%CI: 40.2–61.5). Patients diagnosed in stage III or human immunodeficiency virus (HIV) positive were significantly more likely to die (64.8, 53.4% respectively) during treatment. The frequency of cerebrospinal fluid (CSF) acid-fast-bacilli smear positivity was 10.0% (95% CI 5.5–17.6), 23.8% (15.2–35.3) for CSF culture positivity, and 22.3% (17.8–27.5) for CSF polymerase chain reaction positivity. We found that the headache, fever, vomiting, and abnormal chest radiograph were the most common symptoms and diagnostic findings among tuberculous meningitis patients. Conclusions Despite anti-tuberculosis treatment, adult tuberculous meningitis has very poor outcomes. The mortality rate of patients diagnosed in stage III or HIV co-infection increased significantly during treatment.

Abstract Background It has been reported that the development of cervical squamous cell carcinoma (CSCC) requires the involvement of a large number of lncRNAs. In a recent study lncRNA, WT1-AS was been characterized as a tumor-suppressive lncRNA in gastric cancer. In our study we aim to explore the involvement of WT1-AS in CSCC. Methods Seventy-six CSCC patients (20 to 63 years, 40.1 ± 6.1 year) from the 233 CSCC patients who were admitted by the Affiliated Tumour Hospital of Xinjiang Medical University between august 2010 and January 2014. RT-qPCR, cell proliferation rate measurement, cell transfection, and western blot were carried out to analyze the samples. Results We found that HPV infection failed to affect WT1-AS expression in CSCC tissues, while WT1-AS was down-regulated in CSCC tissues compared with non-cancer tissues. P53 was also down-regulated in CSCC tissues and positively correlated with WT1-AS. Analysis of the survival of CSCC patients revealed that low levels of WT1-AS were accompanied by poor survival. Significantly up-regulated p53 was observed after WT1-AS over-expression in CSCC cells, while p53 over-expression failed to affect WT1-AS. P53 and WT1-AS over-expression resulted in the inhibited proliferation of CSCC cells. Conclusion Therefore, WT1-AS is down-regulated in CSCC and it may inhibit CSCC cell proliferation at least partially by up-regulating p53.

Calonectria species are important plant pathogens on a wide range of hosts, causing significant losses to plant production worldwide. During our survey on phytopathogenic fungi from 2019 to 2021, diseased samples were collected from various hosts in Guangdong Province, China. In total, 16 Calonectria isolates were obtained from leaf spots, stem blights and root rots of species of Arachis, Cassia, Callistemon, Eucalyptus, Heliconia, Melaleuca and Strelitzia plants. Isolates were identified morphologically, and a multigene phylogenetic analysis of combined partial sequences of calmodulin (cmdA), translation elongation factor 1-alpha (tef1-α) and beta-tubulin (β-tubulin) was performed. These sixteen isolates were further identified as nine Calonectria species, with five new species: Ca. cassiae, Ca. guangdongensis, Ca. melaleucae, Ca. shaoguanensis and Ca. strelitziae, as well as four new records: Ca. aconidialis from Arachis hypogaea, Ca. auriculiformis from Eucalyptus sp., Ca. eucalypti from Callistemon rigidus, and Ca. hongkongensis from Eucalyptus gunnii. Moreover, we provide updated phylogenetic trees for four Calonectria species complexes viz. Ca. colhounii, Ca. cylindrospora, Ca. kyotensis and Ca. reteaudii. Our study is the first comprehensive study on Calonectria species associated with various hosts from subtropical regions in China. Results from the present study will be an addition to the biodiversity of microfungi in South China.

Alpine vegetation on the Southwestern Tibetan Plateau (SWTP) is sensitive and vulnerable to climate change and human activities. Climate warming and human actions (mainly ecological restoration, social-economic development, and grazing) have already caused the degradation of alpine grasslands on the Tibetan Plateau (TP) to some extent. However, it remains unclear how human activities (mainly grazing) have regulated vegetation variation under climate change and ecological restoration since 2000. This study used the normalized difference vegetation index (NDVI) and social statistic data to explore the spatiotemporal changes and the relationship between the NDVI and climatic change, human activities, and grazing intensity. The results revealed that the NDVI increased by 0.006/10a from 2000 to 2020. Significant greening, mainly distributed in Rikaze, with partial browning, has been found in the SWTP. The correlation analysis results showed that precipitation is the most critical factor affecting the spatial distribution of NDVI, and the NDVI is correlated positively with temperature and precipitation in most parts of the SWTP. We found that climate change and human activities co-affected the vegetation change in the SWTP, and human activities leading to vegetation greening since 2000. The NDVI and grazing intensity were mainly negatively correlated, and the grazing caused vegetation degradation to some extent. This study provides practical support for grassland use, grazing management, ecological restoration, and regional sustainable development for the TP and similar alpine areas.