Search

Examination of living populations and herbarium specimens (including type material) of Rohdea yunnanensis and R. fargesii has revealed that the two species are morphologically very distinct from each other. We therefore reinstate the independent specific status of R. yunnanensis which has been placed in synonymy with R. fargesii var. fargesii. In former species, the blade margin denticulate; bract base branched or erose; perianth lobe also erose and denticulate; fruit conical and seed reniform, hilum oblique.

Rohdea rotiformis is described and illustrated as a new species from Sichuan province of China. The new species possesses a cushionlike, ringed, fleshy appendage above the stamens in perianth throat. In these features, the new species is morphologically similar to R. urotepala but differs in its ringed appendage surface smooth without verruculose.

Fish are often faced with selection pressure from human activities (e.g., fish angling). Therefore, morphological, physiological, personality, and life history characteristics have evolved directly in fish populations under this human-made selection. Here, we investigate the phenotypic basis of vulnerability to angling in juvenile Qingbo (Spinibarbus sinensis). The standard metabolic rate (SMR), maximum metabolic rate (MMR), and personality (i.e., exploration, activity and boldness) of juvenile S. sinensis were determined. An angling experiment was then conducted and the hormones (i.e., ghrelin) of the individuals were examined in a laboratory at 24.9 ± 0.1 °C. Our results showed that only frequency with which the fish touched the novel object in exploration was higher in the LVA (low vulnerability to angling) phenotype than the HVA (high vulnerability to angling) phenotype, but energy metabolism (SMR; MMR; AS, aerobic scope; FAS, factorial aerobic scope), hormone (ghrelin levels) and personality (exploration, activity and boldness) did not differ between the HVA and the LVA phenotype. Principal components analysis showed that exploration was associated with boldness while activity was not associated with boldness. The AS, exploration and boldness score were inhibitory factors for the HVA outcomes, but ghrelin, activity score and exploration score did not contribute to outcomes of the HVA. These results suggest that energy metabolism, hormone levels and personality are not predictors of vulnerability to angling in Qingbo under the laboratory condition, but individuals with higher tendency to explore the novel environment are more likely to be bolder.

Fangmin Li,1 Xue Li,2 Hui Kou2 1School of Psychological and Cognitive Sciences, Peking University, Beijing, People’s Republic of China; 2Research Center of Humanities and Medicine in School of Management, Zunyi Medical University, Zunyi, Guizhou, People’s Republic of ChinaCorrespondence: Xue Li; Hui Kou, Center for Mental Health Research in School of Management, Zunyi Medical University, Xuefu West Road #6, Zunyi, Guizhou, People’s Republic of China, Tel +86 15772118288 ; +86 17784820423, Email 2224164224@qq.com; kouhuizmu@163.comObjective: Juvenile delinquents have deficits in emotional recognition that might play a critical role in the development of aggression. The present study aimed to investigate the effect of emotional recognition training and its consequences on emotional attention and aggression.Methods: Seventy-three male juvenile delinquents were randomly assigned to two groups. One group was the modification group, which received eight days of training on an emotional recognition task. The purpose of the training was to modify interpretative biases in emotion recognition to encourage the perception of happiness over anger in ambiguous expressions. The other group was the waitlist group, which did not perform a task and continued with their usual programme. Before and after the training, participants completed the aggression questionnaire (AQ) and two behavioural tasks, including the emotional recognition task and a visual search task with happy and angry faces as targets.Results: The modification group recognized more faces as happy after emotional recognition training than the waitlist group. Furthermore, the hostility in the modification group decreased significantly. Importantly, emotional recognition training further affected attention to emotional faces as participants responded faster in searching for happy and angry faces after training.Conclusion: Emotional recognition training could modify juvenile delinquents’ emotional recognition, enhance their visual attention to emotional faces and reduce hostility.Keywords: emotional recognition training, juvenile delinquents, emotional attention, aggression

Arbuscular mycorrhizal (AM) symbiosis is a widespread, ancient mutualistic association between plants and fungi, and facilitates nutrient uptake into plants. Cell surface receptor-like kinases (RLKs) and receptor-like cytoplasmic kinases (RLCKs) play pivotal roles in transmembrane signaling, while few RLCKs are known to function in AM symbiosis. Here, we show that 27 out of 40 AM-induced kinases (AMKs) are transcriptionally upregulated by key AM transcription factors in Lotus japonicus. Nine AMKs are only conserved in AM-host lineages, among which the SPARK-RLK-encoding gene KINASE3 (KIN3) and the RLCK paralogues AMK8 and AMK24 are required for AM symbiosis. KIN3 expression is directly regulated by the AP2 transcription factor CTTC MOTIF-BINDING TRANSCRIPTION FACTOR1 (CBX1), which regulates the reciprocal exchange of nutrients in AM symbiosis, via the AW-box motif in the KIN3 promoter. Loss of function mutations in KIN3, AMK8, or AMK24 result in reduced mycorrhizal colonization in L. japonicus. AMK8 and AMK24 physically interact with KIN3. KIN3 and AMK24 are active kinases and AMK24 directly phosphorylates KIN3 in vitro. Moreover, CRISPR-Cas9-mediated mutagenesis of OsRLCK171, the sole homolog of AMK8 and AMK24 in rice (Oryza sativa), leads to diminished mycorrhization with stunted arbuscules. Overall, our results reveal a crucial role of the CBX1-driven RLK/RLCK complex in the evolutionarily conserved signaling pathway enabling arbuscule formation.

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line–derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q–globular C1Q receptor recognition and subsequent stimulation of transforming growth factor β1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.

In brief Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice. Abstract Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2–Bax–Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.

Biothiols play essential roles in balancing the redox state and modulating cellular functions. Fluorescent probes for monitoring/labelling biothiols often suffer from slow reaction rates, strong background fluorescence and cytotoxic byproduct release. Thus, developing facile and versatile probes to overcome the challenges is still in high demand. Here, we report four coumarin-maleimides as fast responding and fluorogenic probes to detect GSH or label peptides/proteins. The probes quantitatively and selectively react with GSH

In recent years, in response to the call for energy conservation and emission reduction, the air source heat pump systems have been widely applied in regional centralized heating engineering.However, due to the existence of cold island effect, the heat pump unit operation in winter has the problems of low efficiency, high operation cost and insufficient production.This paper takes the heat source station combined with gas source heat pump and electric boiler as an example, and its heat pump unit array was simulated and calculated by analyzing relevant test data and using the numerical calculation method. Some technical measures were put forward to improve the cold island effect, and then the advantages and application scope of these measures are also analyzed.

Integration of chimeric antigen receptor T (CAR-T) cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an emerging technology for B-cell acute lymphoblastic leukemia (B-ALL) treatment with unknown impact on HSCT-related complications. We performed a retrospective cohort study of patients receiving CD19/CD22 dual-targeting or CD19 single-targeting CAR-T therapy before HSCT (CD19/CD22 dual-targeting CAR-T group and CD19 single targeting CAR-T group, respectively), and patients did not receive CAR-T therapy before transplantation (non-CAR-T group). Cumulative incidence of platelet engraftment on day 28 was lower in the CD19/CD22 dual-targeting CAR-T group compared to other groups (p=0.028) and it was proved to be an independent risk factor for delayed platelet recovery on day 28 (OR: 2.65; p=0.001). The CD19/CD22 dual-targeting CAR-T bridging to HSCT independently increases risk of early CMV-viremia (HR, 2.96; p=0.001). Both CAR-T groups had higher incidence of 100-day Epstein-Barr virus (EBV)-viremia, compared with the non-CAR-T group (p=0.043 and p=0.001, respectively). Patients receiving CAR-T cell therapy had a higher risk for early EBV-viremia (HR, 6.77; p=0.030). Relapse and survival did not differ between the 3 groups (p>0.05). Integrating CD19/CD22 dual-targeting CAR-T therapy and HSCT delays platelet engraftment and increases the risks of early CMV- and EBV-viremia.

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

Background Keloids represent one extreme of aberrant dermal wound healing and are characterized by fibroblast hyperproliferation and excessive deposition of extracellular matrix. Genetics is a major factor for predisposition to keloids and genome-wide association study has identified a single-nucleotide polymorphism (SNP) rs873549 at 1q41 as a susceptibility locus. The SNP rs873549, and the SNPs in strong linkage disequilibrium (LD) with rs873549, may be involved in keloid development. However, the functional significance of these SNPs in keloid pathogenesis remains elusive. Objectives To investigate the function and mechanism of SNP rs873549 and the SNPs in strong LD with rs873549 in keloids. Methods SNPs in strong LD with rs873549 were analysed using Haploview. The expression levels of the genes near the susceptibility locus were analysed using quantitative real-time polymerase chain reaction. The interaction between rs1348270-containing enhancer and the long noncoding RNA down expressed in keloids (DEIK) (formerly RP11-400N13.1) promoter in fibroblasts was investigated using chromosome conformation capture. The enhancer activity of the rs1348270 locus was evaluated using luciferase reporter assay. Knockdown experiments were used to explore the function of DEIK in keloids. RNA-Seq was performed to investigate the mechanism by which DEIK regulates the expression of collagens POSTN and COMP. Results rs1348270, an enhancer-located SNP in strong LD with rs873549, mediated looping with the promoter of DEIK. The risk variant was associated with decreased enhancer–promoter interaction and DEIK down-expression in keloids. Mechanistically, downregulation of DEIK increased the expression of collagens POSTN and COMP through upregulating BMP2. Furthermore, correlation analysis revealed that DEIK expression was inversely correlated with BMP2, POSTN and COMP expression in both keloid and normal fibroblasts. Conclusions Our findings suggest that the risk variant rs1348270 is located in an enhancer and is associated with the downregulation of DEIK in keloids, and that downregulation of DEIK increases the expression of collagens POSTN and COMP through BMP2 in keloid fibroblasts. These findings will help to provide a more thorough understanding of the role played by genetic factors in keloid development and may lead to new strategies for screening and therapy in keloid-susceptible populations.

The top priority in drug development is to identify novel and effective drug targets. In vitro assays are frequently used for this purpose; however, traditional experimental approaches are insufficient for large-scale exploration of novel drug targets, as they are expensive, time-consuming and laborious. Therefore, computational methods have emerged in recent decades as an alternative to aid experimental drug discovery studies by developing sophisticated predictive models to estimate unknown drugs/compounds and their targets. The recent success of deep learning (DL) techniques in machine learning and artificial intelligence has further attracted a great deal of attention in the biomedicine field, including computational drug discovery.This study focuses on the practical applications of deep learning algorithms for predicting druggable proteins and proposes a powerful predictor for fast and accurate identification of potential drug targets.Using a gold-standard dataset, we explored several typical protein features and different deep learning algorithms and evaluated their performance in a comprehensive way. We provide an overview of the entire experimental process, including protein features and descriptors, neural network architectures, libraries and toolkits for deep learning modelling, performance evaluation metrics, model interpretation and visualization.Experimental results show that the hybrid model (architecture: CNN-RNN (BiLSTM) + DNN; feature: dictionary encoding + DC_TC_CTD) performed better than the other models on the benchmark dataset. This hybrid model was able to achieve 90.0% accuracy and 0.800 MCC on the test dataset and 84.8% and 0.703 on a nonredundant independent test dataset, which is comparable to those of existing methods.We developed the first deep learning-based classifier for fast and accurate identification of potential druggable proteins. We hope that this study will be helpful for future researchers who would like to use deep learning techniques to develop relevant predictive models.

Purpose: Despite approval of B-cell lymphoma (BCL)-2 inhibitor venetoclax for certain hematologic malignancies, its broader clinical benefit is curtailed by resistance. Our study aimed to determine if treatment with novel anticancer agents targeting BCL-2 and mouse double minute 2 (MDM2) could overcome venetoclax resistance in preclinical models. Experimental Design: Venetoclax-sensitive and venetoclax-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia cells and xenograft models were used to evaluate antitumor effects and underlying mechanisms associated with combined BCL-2 inhibitor lisaftoclax (APG-2575) and MDM2 inhibitor alrizomadlin (APG-115). Results: The combination exhibited synergistic antiproliferative and apoptogenic activities in TP53 wild-type AML cell lines in vitro. This synergy was further exemplified by deep antitumor responses and prolonged survival in AML cell line–derived and patient-derived xenograft models. Interestingly, the combination treatment resensitized (to apoptosis) venetoclax-resistant cellular and mouse models established via chronic drug exposure or genetically engineered with clinically relevant BCL-2 gene mutations. Synergistic effects in reducing cellular viability and proliferation were also demonstrated in primary samples of patients with venetoclax-resistant AML treated with lisaftoclax and alrizomadlin ex vivo. Mechanistically, alrizomadlin likely primes cancer cells to BCL-2 inhibition-induced cellular apoptosis by downregulating expression of antiapoptotic proteins myeloid cell leukemia-1 and BCL–extra-large and upregulating pro-death BCL-2–associated X protein. Conclusions: Lisaftoclax in combination with alrizomadlin overcomes venetoclax resistance mediated by various mechanisms, including BCL-2 mutations. In addition, we posit further, putative molecular mechanisms. Our data rationalize clinical development of this treatment combination in patients with diseases that are insensitive or resistant to venetoclax.

Natural products provides valuable starting points for new drugs with unique chemical structures. Here we retrieve and join LOTUS natural product database and ChEMBL interaction database to explore the relations and rhythm between chemical features of natural products and biotarget spaces. Our analysis revealed relations between the biogenic pathways of natural products and species taxonomy. The data analysis revealed that the N atom was the privileged structure of a highly active natural product. An apparent trend exists in the target space of natural products originating from different biological sources. Alkaloids focused on neurological effects. Oligopeptides and polyketides were mainly associated with protein phosphorylation and HDAC receptors. Fatty acids readily intervene in various physiological processes involving Prostanoids and Leukotrienes. We also used FusionDTA, a deep learning model, to predict the affinity between all LOTUS natural products and 622 therapeutic drug targets, exploring the potential target space for natural products. Our data exploration provided a global perspective on the gaps in the chemobiological space of natural compounds through systematic analysis and prediction of their target space, which can be used for new drug design or natural drug repurposing.

Peer reviewed: True, Acknowledgements: We want to thank the Lee Lab, the FinnGen study, the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), and the Genetic Epidemiology Research on Aging (GERA) for sharing data. XL: the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001). XYW: National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province(2019SK2041); SCL: the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019–00977), and the Swedish Cancer Society (Cancerfonden). Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication., Funder: Cancerfonden; FundRef: http://dx.doi.org/10.13039/501100002794, BACKGROUND: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. METHODS: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. RESULTS: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. CONCLUSIONS: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. FUNDING: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

The southern Great Xing’an Range (SGXR), located in the eastern segment of the Central Asian Orogenic Belt (CAOB), is one of the most economically important Cu–Mo–Fe–Sn–Pb–Zn–Ag metallogenic provinces in China. The newly discovered Panjiaduan Cu–Pb–Zn deposit (9.3 Mt; at 1.36% Cu, 2.90% Pb, 3.80% Zn and 38.12 g/t Ag), located in the SE segment of the SGXR, is primarily hosted in fracture zones in volcanic rocks and granodiorite of the Manitu Formation. Four paragenetic stages of metallic mineralization are identified: (I) quartz-pyrite-arsenopyrite; (II) quartz-polymetallic sulphide; (III) quartz-galena-sphalerite-argentite; and (IV) quartz-calcite-minor sulphide. The hydrothermal quartz contains three types of primary fluid inclusion (FIs): vapour-rich two-phase liquid-vapour (LV-type), liquid-rich two-phase liquid-vapour (VL-type) and three-phase liquid-vapour-solid FIs (SL-type). Stages I and II contain all types with homogenization temperatures (Th) of 324–386 °C and 276–334 °C as well as salinities of 0.7–38.0 wt% and 0.9–34.7 wt%, respectively, whereas stage III is composed of VL- and LV-type FIs with Th of 210–269 °C and salinities of 0.5–7.2 wt%. Only VL-type FIs occur in stage IV, with Th of 139–185 °C and salinities of 1.6–4.2 wt%. The δ18OH2O and δD values vary from −15.7 to 2.6‰ and −132.7 to −110.2‰, respectively, indicating predominant meteoric water with an initial magmatic source. The He–Ar isotopic compositions of the pyrite inclusions from the Panjiaduan Cu–Pb–Zn veins suggest that fluids were derived from the crust.

Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily.This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF.Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32.We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm.The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082).

Three new isochromenes, (5-methoxy-7-prenyl-1H-isochromen-3-yl)methanol (1), 3-(3-(hydroxymethyl)-5-methoxy-1H-isochromen-7-yl)propan-1-ol (2), and (5-methoxy-7-methyl-1H-isochromen-3-yl)methanol (3), along with three known analogues (4–6) were isolated from the fermentation products of a Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor. Their structures were elucidated by spectroscopic methods, including extensive 1 D and 2 D NMR techniques. Compounds 1–3 and 6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 46.4%, and this rate is higher than that of positive control. Compounds 1, 3, and 6 also showed potential anti-TMV activity with inhibition rates of 28.6, 30.5, and 26.2%, respectively. The IC50 of compounds 1–3 and 6 were also tested, and showed IC50 values of 49.3, 22.4, 42.2, and 54.1 µM, respectively.

The plant-specific family of WUSCHEL (WUS)-related homeobox (WOX) transcription factors is key regulators of embryogenesis, meristem maintenance, and lateral organ development in flowering plants. The modern/WUS clade transcriptional repressor STENOFOLIA/LAMINA1(LAM1), and the intermediate/WOX9 clade transcriptional activator MtWOX9/NsWOX9 antagonistically regulate leaf blade expansion, but the molecular mechanism is unknown. Using transcriptome profiling and biochemical methods, we determined that NsCKX3 is the common target of LAM1 and NsWOX9 in Nicotiana sylvestris. LAM1 and NsWOX9 directly recognize and bind to the same cis-elements in the NsCKX3 promoter to repress and activate its expression, respectively, thus controlling the levels of active cytokinins in vivo. Disruption of NsCKX3 in the lam1 background yielded a phenotype similar to the knockdown of NsWOX9 in lam1, while overexpressing NsCKX3 resulted in narrower and shorter lam1 leaf blades reminiscent of NsWOX9 overexpression in the lam1 mutant. Moreover, we established that LAM1 physically interacts with NsWOX9, and this interaction is required to regulate NsCKX3 transcription. Taken together, our results indicate that repressor and activator WOX members oppositely regulate a common downstream target to function in leaf blade outgrowth, offering a novel insight into the role of local cytokinins in balancing cell proliferation and differentiation during lateral organ development.

The present study was conducted to explore the entry point of entrepreneurship education by continuously following and investigating the entrepreneurship team of horticulture majors and exploring the integration of entrepreneurship teaching based on the existing professional curriculum and teaching system. We examined the goals of developing a teaching system for horticulture students' entrepreneurial competence training, and we summarized the entry points for horticulture students' entrepreneurial competence training. We discovered that in curriculum design, teachers should pay more attention to leading and engaging students in entrepreneurial thinking, and that entrepreneurial competency training for team students with goals and targets should be provided.

This systematic review examined and synthesized peer-reviewed research studies that reported the process of integrating social determinants of health (SDOH) or social needs screening into electronic health records (EHRs) and the intervention effects in the United States.Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, a systematic search of Scopus, Web of Science Core Collection, MEDLINE, and Cochrane Central Register of Clinical Trials was performed. English language peer-reviewed studies that reported the process of integrating SDOH or social needs screening into EHRs within the U.S. health systems and published between January 2015 and December 2021 were included. The review focused on process measures, social needs changes, health outcomes, and health care cost and utilization.In total, 28 studies were included, and half were randomized controlled trials. The majority of the studies targeted multiple SDOH domains. The interventions vary by the levels of intensity of their approaches and heterogeneities in outcome measures. Most studies (82%,Our review supports the current policy efforts to increase U.S. health systems' investment toward directly addressing SDOH. While effective interventions can be more complex or resource intensive than an online referral, health care organizations hoping to achieve health equity and improve population health must commit the effort and investment required to achieve this goal.

Rapid screening of foodborne pathogens is of great significance to ensure food safety. A microfluidic biosensor based on immunomagnetic separation, enzyme catalysis and electrochemical impedance analysis was developed for rapid and sensitive detection of Salmonella typhimurium. First, the bacterial sample, the magnetic nanoparticles (MNPs) modified with capture antibodies, and the enzymatic probes modified with detection antibodies and glucose oxidase (GOx) were simultaneously injected into the microfluidic chip, followed by mixing and incubation to form MNP-bacteria-probe sandwich complexes. Then, glucose with high impedance was injected into the chip and catalyzed by the GOx on the complexes into hydrogen peroxide with high impedance and gluconic acid with low impedance, which was finally measured using the low-cost interdigitated microelectrode and the electrochemical impedance analyzer to determine the target bacteria. Under the optimal conditions, this biosensor could quantitatively detect Salmonella typhimurium at the concentrations from 1.6 × 102 CFU/mL to 1.6 × 106 CFU/mL in 1 h with the low detection limit of 73 CFU/mL. Besides, this biosensor was demonstrated with good feasibility for practical applications by detecting the Salmonella typhimurium spiked chicken meat samples.

In this study, we undertook zircon U–Pb dating and Hf isotopic and whole-rock geochemical analysis of Mesozoic granites from the Zhalantun and Arxan areas of the Great Xing’an Range, northeastern China. Zircon U–Pb dating of four samples indicates they formed in the Early Cretaceous (ca. 140.7–130.0 Ma). Geochemically, the samples have high silica (74.00–77.29 wt.%) and total alkali (8.52–8.90 wt.%) and low CaO (0.21–0.71 wt.%), MgO (0.06–0.48 wt.%), and P2O5 (0.01–0.06 wt.%) contents and exhibit the weakly peraluminous (A/CNK = 0.98–1.06) and high-K calc-alkaline characteristics, with highly differentiated I-type granite affinities (differentiation index = 93.19–96.93). The studied granites are enriched in light rare earth and large ion lithophile elements and depleted in heavy rare earth and high field strength elements. Their zircon εHf(t) values are mainly positive (+2.49 to +11.64) and yield two-stage Hf model ages of 1023–445 Ma. The geochemical and isotopic data indicate they might have been derived from the partial melting of medium- to high-K basaltic crust material during the Mesoproterozoic to Phanerozoic. They underwent fractional crystallization in the magma evolution process, and K-feldspar and plagioclase were the major crystallization phases. Combined with the temporal–spatial migration of the Mesozoic magmatic events in the whole northeastern China, we propose that the generation of Early Cretaceous highly differentiated I-type granites in the central Great Xing’an Range was associated with the delamination effect caused by the roll-back of the Paleo-Pacific plate.

Targeted therapy has been standardized in front-line therapies for metastatic colorectal cancer (mCRC), while explicit recommendations for third- or later-line are still lacking. This study evaluated the efficacy and safety of combining targeted therapy with chemotherapy in the third- or later-line treatment for mCRC via meta-analysis, providing evidence-based guidance for clinical or research practice. Comprehensive retrieval of related studies was conducted according to the PRISMA guideline. Studies were stratified with patient characteristics and pharmacological classification of the drugs. For the data available for quantitative analysis, pooled overall response rate, disease control rate, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and adverse events rate with respective 95% confidence intervals (CIs) were calculated. A total of 22 studies (1,866 patients) were included in this meta-analysis. Data from 17 studies (1,769 patients) involving targets of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) were extracted for meta-analyses. The overall response rates for monotherapy and combined therapy were 4% (95% CI: 3%, 5%) and 20% (95% CI: 11%, 29%). The pooled HRs (combined therapy vs. mono) for OS and PFS were 0.72 (95% CI: 0.53, 0.99) and 0.34 (95% CI: 0.26, 0.45). Another five studies were included in narrative depiction, involving targets of BRAF, HER-2, ROS1, and NTRK. The findings of this meta-analysis indicate that VEGF and EGFR inhibitors manifest promising clinical response rates and prolonged survival in the treatment of mCRC with acceptable adverse events.

Post-transcriptionally RNA modifications, also known as the epitranscriptome, play crucial roles in the regulation of gene expression during development. Recently, deep learning (DL) has been employed for RNA modification site prediction and has shown promising results. However, due to the lack of relevant studies, it is unclear which DL architecture is best suited for some pyrimidine modifications, such as 5-methyluridine (m5U). To fill this knowledge gap, we first performed a comparative evaluation of various commonly used DL models for epigenetic studies with the help of autoBioSeqpy. We identified optimal architectural variations for m5U site classification, optimizing the layer depth and neuron width. Second, we used this knowledge to develop Deepm5U, an improved convolutional-recurrent neural network that accurately predicts m5U sites from RNA sequences. We successfully applied Deepm5U to transcriptomewide m5U profiling data across different sequencing technologies and cell types. Third, we showed that the techniques for interpreting deep neural networks, including LayerUMAP and DeepSHAP, can provide important insights into the internal operation and behavior of models. Overall, we offered practical guidance for the development, benchmark, and analysis of deep learning models when designing new algorithms for RNA modifications.