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Background: Dietary antioxidants have been found to improve various diseases, including digestive, cardiovascular, and urinary disorders. However, the relationship between CDAI and constipation remains unclear. This study aims to investigate the potential link between CDAI and constipation among adults in the United States., Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2005 and 2010. Dietary data from the respondents were obtained through two 24-hour dietary recall interviews. Multiple statistical methods, including multivariable logistic regression, subgroup analysis, and smooth curve fitting analysis, were used to explore the association between CDAI and chronic constipation., Results: A total of 10,904 participants were included in the study, of whom 1,184 were identified as having chronic constipation. After adjusting for potential confounders, multivariable logistic regression analysis showed that higher CDAI was significantly associated with a lower risk of constipation (OR = 0.958 [0.929, 0.987]). Compared to the lowest quartile, the highest quartile of CDAI was associated with a significantly reduced prevalence of constipation (OR = 0.704 [0.535, 0.927]). Subgroup analysis indicated that differences in gender, alcohol intake, and smoking status might influence the association between CDAI and constipation. Smooth curve analysis revealed an "n" shaped relationship between CDAI and constipation among non-alcohol consumers, with a turning point at a CDAI value of 1.08., Conclusion: An elevated CDAI is negatively correlated with the incidence of chronic constipation, suggesting that increasing dietary antioxidant intake may reduce constipation prevalence. These findings underscore the importance of dietary antioxidants in maintaining gut health and provide comprehensive guidance for clinical and public health practices., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Implantable sensors, especially ion sensors, facilitate the progress of scientific research and personalized healthcare. However, the permanent retention of implants induces health risks after sensors fulfill their mission of chronic sensing. Biodegradation is highly anticipated; while; biodegradable chemical sensors are rare due to concerns about the leakage of harmful active molecules after degradation, such as ionophores. Here, a novel biodegradable fiber calcium ion sensor is introduced, wherein ionophores are covalently bonded with bioinert nanoparticles to replace the classical ion-selective membrane. The fiber sensor demonstrates comparable sensing performance to classical ion sensors and good flexibility. It can monitor the fluctuations of Ca 2+ in a 4-day lifespan in vivo and biodegrade in 4 weeks. Benefiting from the stable bonding between ionophores and nanoparticles, the biodegradable sensor exhibits a good biocompatibility after degradation. Moreover, this approach of bonding active molecules on bioinert nanoparticles can serve as an effective methodology for minimizing health concerns about biodegradable chemical sensors., (© 2024 Wiley‐VCH GmbH.)

Background: Lung cancer is the leading prevalent form of human cancer and has the highest mortality rate among all cancer types. The role and potential mechanism of the lung microbiome in lung cancer is still unknown. This study aims to investigate the microbiomes of lung cancer patients possessing different levels of infiltrated CD8 + T cells and programmed cell death-1 (PD-1) receptors, and further assess the correlation between specific microbes and the immune environment of lung tumor., Methods: We analyzed the microbiomes of lung cancer tissues from patients with different levels of infiltrated CD8 + T cells and PD-1 expression using 16S rRNA gene sequencing. The relative abundance of dominant phyla and genera was compared, and the correlation between microbial composition and immune markers was explored., Results: Our results showed that lung cancer tissues displayed similar microbiome profiles, including Proteobacteria, Bacteroidetes, and Actinobacteria as the dominant phyla; and Chryseobacterium, Triticum aestivum (bread wheat), and Acinetobacter as the dominant genera. We found that the relative abundance of Chryseobacterium was positively correlated with CD8 + T cell infiltration and the level of PD-1 expression, while the relative abundance of Acinetobacter was negatively associated with the PD-1 level. In addition, higher beta diversity was identified in samples with low CD8 + T cell infiltration, but no significant correlation between beta diversity and PD-1 expression was observed. Furthermore, the relative abundance of Cyanobacteria was significantly higher in both the CD8 high and PD-1 high groups., Conclusions: Our study indicated that the lung microbiota played an indispensable role in the CD8 + T cell-mediated tumor immune response. These findings shed light on valuable insights into the intricate interplay between the lung microbiome and the immune system in the progression of lung cancer, offing potential therapeutic strategies targeting the lung microbiome., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-107/coif). All authors report this study was funded by Shenzhen Science and Technology R&D Funds-Basic Research (Key Project) (No. JCYJ20200109120208018) and 2024 Hospital-Level Clinical Research Key Project of Shenzhen Second People’s Hospital (No. 20243357014). The authors have no other conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Background: Acute myocardial infarction (AMI) is characterized by inflammation, oxidative stress, and atherosclerosis, contributing to increased mortality risk. High-density lipoprotein (HDL) takes a crucial part in mitigating atherosclerosis and inflammation through its diverse functionalities. Conversely, fibrinogen is implicated in the development of atherosclerotic plaques. However, the mortality risk predictive capacity of fibrinogen to HDL-cholesterol ratio (FHR) in AMI patients remains unexplored. This research aimed to evaluate the effectiveness of FHR for mortality risk prediction in relation to AMI., Methods: A retrospective study involving 13,221 AMI patients from the Cardiorenal ImprovemeNt II cohort (NCT05050877) was conducted. Baseline FHR levels were used to categorize patients into quartiles. The assessment of survival disparities among various groups was conducted by employing Kaplan‒Meier diagram. Cox regression was performed for investigating the correlation between FHR and adverse clinical outcomes, while the Fine-Gray model was applied to evaluate the subdistribution hazard ratios for cardiovascular death., Results: Over a median follow-up of 4.66 years, 2309 patients experienced all-cause death, with 1007 deaths attributed to cardiovascular disease (CVD). The hazard ratio (HR) and its 95% confidence interval (CI) for cardiac and all-cause death among individuals in the top quartile of FHR were 2.70 (1.99-3.65) and 1.48 (1.26-1.75), respectively, in comparison to ones in the first quartile, after covariate adjustment. Restricted cubic spline analysis revealed that FHR was linearly correlated with all-cause mortality, irrespective of whether models were adjusted or unadjusted (all P for nonlinearity > 0.05)., Conclusion: AMI patients with increased baseline FHR values had higher all-cause and cardiovascular mortality, regardless of established CVD risk factors. FHR holds promise as a valuable tool for evaluating mortality risk in AMI patients., Trial Registration: The Cardiorenal ImprovemeNt II registry NCT05050877., (© 2024. The Author(s).)

Background: Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor., Methods: In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts., Results: MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response., Conclusions: MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use., (© 2023. The Author(s).)

Background: Hyperglycemia has been associated with an adverse prognosis in patients with premature coronary artery disease (CAD). However, whether the intermediate hyperglycemia status affects the risk of mortality in premature CAD patients treated with percutaneous coronary intervention (PCI), remains unclear., Methods: We retrospectively included 14,585 premature CAD patients undergoing PCI from 2007 to 2020. Patients were divided into normal glycemia ( < 6%), intermediate hyperglycemia (6%-6.5%), and hyperglycemia ( ≥ 6.5%) according to hemoglobin A1c (HbA1c) level in whole blood. Follow-up all-cause mortality was defined as a primary outcome, and Cox proportional regression analysis was used to assess the association between glycemia status and the primary outcome., Results: Among 14,585 premature CAD patients undergoing PCI (mean age 43.6 ± 7.6 years, 28.1% female), 2856 (19.6%) were diagnosed with intermediate hyperglycemia. Over a median follow-up of 4.62 years (2.72-7.19 years), patients with hyperglycemia were correlated with higher risk (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.19-1.54, p < 0.001) while patients with intermediate hyperglycemia were associated with intermediate mortality risk from all causes (HR 1.17, 95% CI 1.0-1.36, p = 0.049)., Conclusions: Intermediate hyperglycemia was positively associated with all-cause mortality risk in patients with premature CAD undergoing PCI. Active glucose-lowering therapy may be considered in these patients., Clinical Trial Registration: NCT05050877., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their role in physiological and pathological contexts within tissues is just beginning to be appreciated. In this review, we showcase recent studies on the splicing and AS of key genes in metabolic pathways in the liver, the effect of metabolic signals on the spliceosome, and therapeutic intervention points based on RNA splicing., Competing Interests: Declaration of interests A.M.J., S.Y., H.A.B.P., and S.V. are inventors on a patent covering the use of SSOs to modify liver metabolism. I.C.’s partner has stock options in Ochre Bio. The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC 0-24 ) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC 0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure ( P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments., Competing Interests: The authors declare no conflict of interest.

Aim: Cardiac biomarkers' predictive value of contrast-associated acute kidney injury (CA-AKI) remains unclear. We analysed whether creatine kinase isoenzyme-MB (CKMB), cardiac troponin I (cTnI) and preoperative N-terminal pro-brain natriuretic peptide (NT-proBNP) are tied to CA-AKI patients undergoing cardiac catheterization., Methods: In the multi-center study, we included 3553 people underwent cardiac catheterization for analysis. CA-AKI was defined as the absolute increase of over 0.3 mg/dL or an increase of more than 50% compared with the baseline serum creatinine within 48 hours following cardiac catheterization. Logistic regression model and receiver operating characteristic (ROC) curves were used to examine the association between cardiac biomarkers and CA-AKI and the efficacy of Mehran risk score (MRS) model on CA-AKI prediction with and without cardiac biomarkers., Results: Among 3553 people, 200 people eventually developed CA-AKI. The logistic regression model showed that log 10 CKMB (odds ratio (OR): 1.97, 95%CI:1.51-2.57, p < .001), cTnI (OR: 1.03, 95%CI: 1.02-1.04, p < .001) and log 10 NT-proBNP (OR: 3.19, 95%CI: 2.46-4.17, p < .001) were independent predictors of CA-AKI. The ROC curve demonstrated that area under the curve (AUC) of MRS was 0.733. CKMB, cTnI and NT-proBNP all significantly improved the AUC value in combination with MRS model. (NT-proBNP: 0.798, p < .001; CKMB: 0.758, p = .003; cTnI: 0.755, p = .002), among which the NT-proBNP had the best predictive efficacy improvement., Conclusion: Cardiac biomarkers of CKMB, cTnI and NT-proBNP are all independently associated with CA-AKI among patients undergoing cardiac catheterization while NT-proBNP remains the best indicator. Adding CKMB, cTnI and NT-proBNP to MRS improved the prognostic efficacy and may be considered effective tools to predict the risk of CA-AKI in clinical practice., (© 2023 Asian Pacific Society of Nephrology.)

Background: Patients with secondary mitral regurgitation (sMR) often present with greater mortality and comorbidity, which may be predicted by some risk factors. This study was designed to investigate the prognostic meaning of the echocardiographically detected wall motion score index (WMSI) in coronary artery disease (CAD) patients with moderate or severe baseline sMR who underwent percutaneous coronary intervention (PCI) therapy., Methods: The present study was a multi-center and prospective cohort of consecutive CAD patients with baseline moderate or severe sMR who underwent PCI. All underwent echocardiography at baseline and at follow-up after PCI to assess sMR and WMSI. The primary endpoint was the persistence of moderate or severe sMR after the second echocardiographic measurement. Logistic and Cox proportional hazards models were constructed for the primary (persistent moderate or severe sMR) and secondary (worsening heart failure [HF]; all-cause mortality; cardiovascular-specific mortality; and major adverse cardiovascular events [MACE]) endpoints., Results: Among 920 participants, 483 had WMSI values of ≥ 1.47, and 437 were less. Of all the participants, 366 (39.8%) continued to have moderate or severe sMR after the second echocardiogram measurement. After full adjustment for confounders, elevated WMSI after PCI was independently associated with the primary endpoint during 3-12 month follow-up. Similarly, elevated WMSI was associated with increased risk of worsening HF, all-cause mortality, cardiovascular-specific mortality, and MACE., Conclusions: Persistent moderate or severe sMR is common (approximately 40%) in PCI patients. Elevated WMSI in CAD patients after PCI is a predictor of persistent moderate or severe sMR and has independent negative prognostic value. Patients with CAD and sMR should be monitored for WMSI to identify those at higher risk of mortality and comorbidity., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs., (© 2023 John Wiley & Sons Ltd.)

Objective: Pharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome., Design: Prospective diagnostic accuracy study., Setting: Inpatient wards and outpatient clinics, northern Tanzania., Patients: Children aged 4-17 years were consecutively recruited on initiation of WHO-approved treatment regimens., Interventions: Samples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC 0-24 ); urine at post-dose intervals of 0-4, 4-8 and 8-24 hours, with rifampin excretion amount measured onsite by spectrophotometry., Main Outcome Measures: Receiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC 0-24 target of 31.7 mg*hour/L., Results: 89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC 0-24 target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC 0-24 target was 69.3% (95% CI 56.7% to 81.8%), p=0.007., Conclusions: Urine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute kidney disease (AKD) following coronary angiography (CAG) indicates a higher risk of chronic kidney disease and follow-up cardiovascular comorbidities. However, the predictive risk factor of AKD is not clear. We sought to verify whether preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was associated with AKD in patients undergoing CAG., Method: We analyzed 7602 patients underwent CAG in this multi-center registry cohort study. Cardiorenal ImprovemeNt II (CIN-II) in five Chinese tertiary hospitals from 2007 to 2020. The primary outcome was AKD, defined as a ≥ 50% increase of serum creatinine within 7-90 days. Multivariable logistic regressions were used to assess the association between NT-proBNP and AKD., Result: 1009 patients (13.27%) eventually developed AKD, who were more likely to be female, older, and with comorbidities of chronic heart failure and anemia. After adjusting to the potential confounders, the NT-proBNP level remained an independent predictor of AKD (lnNT-proBNP OR: 1.20, 95% CI 1.13-1.28, p < 0.005). Restricted cubic spline analysis demonstrated a linear relationship between elevated NT-proBNP and AKD (p for trend < 0.001). In the subgroup analysis, elevated NT-proBNP level in patients with percutaneous coronary intervention (p for interaction < 0.001) or without previous congestive heart failure (p for interaction = 0.0346) has a more significant value of AKD prediction., Conclusion: Pre-operative NT-proBNP level was independently associated with the risk of AKD in patients following CAG. Perioperative strategies are warranted to prevent AKD in patients with elevated NT-proBNP levels., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute kidney injury (AKI) is a common complication after acute myocardial infarction (AMI) in clinical practice, and the majority of previous preclinical models were induced by a single factor. The objective of the present study was to establish a stable preclinic model of AKI induced by contrast media (CM) with acute myocardial ischemia reperfusion surgery and to identify the effect of oxidative stress on kidney injury. Rats were treated individually or with CM or myocardial ischemia reperfusion surgery. Renal baseline and AKI parameters, the level of oxidative stress and histopathological images were examined along with AKI biomarkers. Results showed the incidence of AKI in the CM group and ischemia reperfusion injury (IRI) group was 40%, χ 2 test (P<0.05 vs. CM-IRI) and 35%, χ 2 test (P<0.05 vs. CM-IRI) and the combination group had the highest incidence rate 75%. IRI surgery combined with CM diminished kidney function and induced oxidative stress by increasing creatinine, blood urea nitrogen and reactive oxygen species levels. Western blotting showed that the early AKI biomarker of NGAL and KIM-1 increased and that the combination group had the highest value. Pathology damage exhibited severe kidney damage in the combination group compared with other control groups. The present research established a reliable preclinic model of post-AMI AKI with a stable and high postoperative AKI rate. Additionally, CM was demonstrated to exacerbate AKI caused by acute myocardial infarction through oxidative stress and, thus, oxidative stress may be a potential therapeutic target., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yu et al.)

Purpose: To evaluate how obesity affects the pharmacokinetics of human IgG following subcutaneous (SC) and intravenous (IV) administration to rats and the homeostasis of endogenous rat IgG., Methods: Differences in body weight and size, body composition, and serum concentration of endogenous rat IgG in male Zucker obese (ZUC-FA/FA) and control (ZUC-LEAN) rats were measured from the age of 5 weeks up to 30 weeks. At the age of 23-24 weeks animals received a single IV or SC dose of human IgG (1 g/kg of total body weight), and serum pharmacokinetics was followed for 7 weeks. A mechanistic model linking obesity-related changes in pharmacokinetics with animal growth and changes in body composition was developed., Results: Significant differences were observed in both endogenous and exogenous IgG pharmacokinetics between obese and control groups. The AUC for human IgG was lower in obese groups (57.6% of control after IV and 48.1% after SC dosing), and clearance was 1.75-fold higher in obese animals. The mechanistic population model successfully captured the data and included several major components: endogenous rat IgG homeostasis with age-dependent synthesis rate; competition of human IgG and endogenous rat IgG for FcRn binding and its effect on endogenous rat IgG concentrations following injection of a high dose of human IgG; and the effect of body size and composition (changing over time and dependent on the obesity status) on pharmacokinetic parameters., Conclusions: We identified important obesity-induced changes in the pharmacokinetics of IgG. Results can potentially facilitate optimization of the dosing of IgG-based therapeutics in the obese population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ideal Plant Architecture 1 (IPA1) is a key regulator of plant architecture. However, knowledge of downstream genes applicable for improving rice plant architecture is very limited. We identified the plant architecture regulatory gene NARROW LEAF 11 (NAL11), which encodes a heat-shock protein (HSP) containing a DnaJ domain. A promising rare allele of NAL11 (NAL11 -923del-1552 ) positively selected in Aus cultivars was identified; this allele exhibited increased expression and generated relatively few tillers, thick stems, and large panicles, components of the ideal plant architecture (IPA). NAL11 is involved in regulating the cell cycle and cell proliferation. NAL11 loss-of-function mutants present impaired chloroplast development and gibberellin (GA) defects. Biochemical analyses show that IPA1 directly binds to elements in the missing fragment of the NAL11 -923del-1552 promoter and negatively regulates NAL11 expression. Genetic analyses support the hypothesis that NAL11 acts downstream of IPA1 to regulate IPA by modulating GA homeostasis, and NAL11 may be an essential complement for IPA1. Our work revealed that avoidance of the inhibition of NAL11 -923del-1552 caused by IPA1 represents a positive strategy for rescuing GA defects accompanied by the upregulation of IPA1 in breeding high-yield rice., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

In current ultrafiltration systems, limited removal for small-sized contaminants and membrane fouling remain longstanding obstacles to overcome. Herein, a novel process by simultaneous coupling powered carbon (PC) and fluidized granular activated carbon (GAC) with ultrafiltration was proposed aiming to achieve high effluent quality and mitigated membrane fouling. This study conducted mechanistic explorations on the performances of different-shaped GAC particles on fouling control and PC release during fluidization, meanwhile comparing the utilizations of powdered activated carbon (PAC) and biochar in terms of their adsorption, deposition and interactions with aquatic contaminants during filtration. The results showed that the effluent COD of biochar-UF was slightly higher than PAC-UF attributed to lower specific surface area and pore volume present on biochar. Compared with PAC-UF, the biochar-UF without fluidized GAC exhibited higher fouling propensity due to more organics attached on membranes via bridging with Ca 2+ released by the biochar. Concurrently, distinct morphologies were found for PAC and biochar depositions, where PAC uniformly dispersed on membranes but biochar tended to agglomerate. Interestingly, fluidized spherical GAC (RGAC) with highest particle momentum and least energy consumption appeared highly effective in reducing fouling associated with biochar, and the overall fouling rate of RGAC-biochar-UF was even lower than RGAC-PAC-UF system. More importantly, substantial amount of small-sized PC was released by two cylindrical-shaped GACs, which were determined to be around 12-16 mg/L in contrast to merely 3.4 mg/L produced from RGAC. Consequently, the RGAC-biochar-UF system achieved commensurate effluent quality but better permeability than RGAC-PAC-UF along with a 20% expenditure saved, which might be a promising water treatment system more suitable for large-scale applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The prevalence of prediabetes is increasing in young adults and patients undergoing coronary angiography. However, whether prediabetes is a considerable risk factor for all-cause mortality remains undetermined in young patients undergoing coronary angiography., Methods: In this study, we retrospectively included 8868 young patients (men aged < 45 years, women aged < 55 years) who underwent coronary angiography (CAG). Patients were categorized as normoglycemic, prediabetes and diabetes according to the HbA1c level or documented history of diabetes. The association of all-cause mortality with diabetes and prediabetes was detected by Cox proportional hazards regression analysis., Results: A total of 3240 (36.5%) among 8868 young patients receiving CAG were prediabetes and 2218 (25.0%) were diabetes. 728 patients died during a median follow-up of 4.92 years. Compared to the normoglycemic group, prediabetes increased the risk of all-cause mortality in young CAG patients by 24%(adjusted HR: 1.24, 95% CI: 1.04-1.49, p = 0.019) and diabetes increased the risk of all-cause mortality by 46%(adjusted HR:1.46, 95% CI:1.2-1.79, p < 0.001). Subgroup analysis showed that diabetes and prediabetes increased the risk of death mainly in patients without comorbidities., Conclusion: Prediabetes accounts for more than one-third of the young adults undergoing CAG and was associated with an increased risk of all-cause mortality, active prevention strategy should be considered for these patients., (© 2023. The Author(s).)

Background: Chronic kidney disease (CKD) is inherently a complex immune-inflammatory condition, and heightened inflammation and immune dysfunction are closely related to an increased risk of death. However, evidence regarding the relationship between immune-inflammatory levels and all-cause, cardiovascular, and cancer mortality among patients with CKD is scarce., Methods: Patients with non-dialysis dependent CKD undergoing coronary angiography (CAG) were included from five Chinese tertiary hospitals. Systemic immune inflammation index (SII) was calculated by multiplying peripheral platelet count with neutrophil-to-lymphocyte ratio, and patients were categorized into four groups by SII quartiles. Cox regression models and competing risk Fine and Gray models were used to examining the relationships between SII levels and all-cause, cardiovascular, and cancer mortality., Results: A total of the 19,327 patients (68.8 ± 10.03 years, female 32.0%) were included in this study. During a median follow-up of 4.5 years, 5,174 deaths occurred, including 2,861 cardiovascular deaths and 375 cancer deaths. Controlling for confounders, all-cause mortality (Q2, Q3, Q4: hazard ratio(HR) [95 CI%] = 1.15 [1.06-1.26], 1.30 [1.19-1.42], 1.48 [1.35-1.62], respectively; p for trend < 0.001) and cardiovascular mortality (Q2, Q3, Q4: HR [95 CI%] = 1.16 [1.03-1.31], 1.40 [1.24-1.58], 1.64 [1.44-1.85], respectively; p for trend < 0.001) increased with higher SII levels, and SII levels was related to cancer mortality comparing last quartile to first quartile of SII (Q2, Q3, Q4: HR [95 CI%] = 1.12 [0.83-1.52], 1.22 [0.90-1.67], 1.50 [1.09-2.08], respectively; p for trend < 0.001)., Conclusion: Elevated immune inflammation level on admission was an independent risk factor for all-cause, cardiovascular, and cancer mortality among CKD patients. Further research is needed to validate the predictive value of SII for mortality risk among CKD patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: The aim of this study was to investigate the association of HbA1c and left ventricular (LV) systolic function among patients with coronary artery disease (CAD)., Methods: CAD patients from the Cardiorenal ImprovemeNt II (CIN-II, NCT05050877) registry were included in the study. They were separated into four groups based on HbA1c levels (Q1: HbA1c<5.7%; Q2: 5.7% ≤ HbA1c < 6.1%; Q3: 6.1% ≤ HbA1c < 6.9%; Q4: HbA1c ≥ 6.9%). The endpoint was decline in LV systolic function, defined as an absolute decrease in LV ejection fraction (LVEF) ≥10% from baseline to follow-up with 3-12 months. The association of HbA1c and LVEF was assessed by logistics regression models., Results: CAD patients (n = 3,994) (age 62.9 ± 10.6 years; 22.2% female) were included in the final analysis. A decline in LV systolic function was recorded in 429 (11%) patients during follow-up. After fully adjusting for confounders, HbA1c was significantly associated with the high risk of decline in LV systolic function (OR 1.12 [95%CI 1.05-1.20] P = 0.001). By stratifying HbA1c as four groups, there is a significantly increased risk of decline in LV systolic function when HbA1c ≥6.1% (Q2, Q3 and Q4 vs Q1, with OR 1.22 [0.88-1.68] P = 0.235; OR 1.48 [1.07-2.05] P = 0.019; OR 1.60 [1.160-2.22] P = 0.004, respectively). Meanwhile, patients with decline in LV systolic function had a higher risk of cardiovascular death., Conclusions: Elevated HbA1c is a predictor of decline in LV systolic function in CAD patients. Clinicians should be aware of the risk of decline in LV systolic function in CAD patients with elevated HbA1c, and take measures as soon as possible., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2022. Published by Elsevier Masson SAS.)

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases., (© 2022. The Author(s).)

Purpose: Diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated consistent benefits in the reduction of hospitalization for HF in patients with DM. However, the pharmacological mechanism is not clear. To investigate the mechanisms of SGLT2 inhibitors in DM with HF, we performed target prediction and network analysis by a network pharmacology method., Methods: We selected targets of SGLT2 inhibitors and DM status with HF from databases and studies. The "Drug-Target" and "Drug-Target-Disease" networks were constructed using Cytoscape. Then the protein-protein interaction (PPI) was analyzed using the STRING database. Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to investigate using the Bioconductor tool for analysis., Results: There were 125 effective targets between SGLT2 inhibitors and DM status with HF. Through further screening, 33 core targets were obtained, including SRC, MAPK1, NARS, MAPK3 and EGFR. It was predicted that the Rap1 signaling pathway, MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, AGE-RAGE signaling pathway in diabetic complications and other signaling pathways were involved in the treatment of DM with HF by SGLT2 inhibitors., Conclusion: Our study elucidated the possible mechanisms of SGLT2 inhibitors from a systemic and holistic perspective based on pharmacological networks. The key targets and pathways will provide new insights for further research on the pharmacological mechanism of SGLT2 inhibitors in the treatment of DM with HF., (© 2021. The Author(s).)

Metals are necessary elements for bacteria. Typically, vertebrate hosts restrict invading bacterial pathogens from accessing metals. Therefore, bacteria have evolved high-affinity metal importers to acquire metals. Streptococcus suis is a major swine pathogen and an emerging zoonotic agent that endangers the swine industry and human health worldwide. Herein, we aimed to identify the zinc acquisition systems in S. suis and evaluate their roles in bacterial virulence. Bioinformatic analyses revealed that S. suis encodes homologues of AdcA and AdcAII, two well-characterised Zn-binding lipoproteins in certain streptococci. Quantitative reverse transcription PCR (qRT-PCR) analysis revealed that the expressions of adcA and adcAII were significantly upregulated in response to Zn limitation, with a higher expression level of adcAII than adcA. Gene deletion mutants and complementation strains were constructed; their growth characteristics under Zn-deficient and Zn-replete conditions indicated that AdcA and AdcAII have overlapping functionality in Zn acquisition. A mouse infection model was used to evaluate the roles of AdcA and AdcAII in S. suis virulence. Mice infected with the double mutant ΔadcAΔadcAII exhibited a significantly higher survival rate, decreased bacterial burden, and lower production of inflammatory cytokines compared to those infected with the wild type (WT) strain. Furthermore, ΔadcAΔadcAII showed reduced competitiveness in infection establishment compared with the WT strain. RNA sequencing, qRT-PCR, and electrophoretic mobility shift assays revealed that AdcR negatively regulates the expressions of adcA and adcAII. Collectively, our results demonstrated that AdcA and AdcAII, which are negatively regulated by AdcR, contribute additively to zinc acquisition and virulence in S. suis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Inflammation and immune responses play an important role in the pathophysiology of contrast-associated acute kidney injury (CA-AKI), and systemic immune inflammation index (SII) has recently emerged as a new parameter for immune and inflammatory response evaluation. However, limited research has been undertaken to explore the relationship between SII and CA-AKI following coronary angiography (CAG)., Patients and Methods: From January 2007 to December 2020, 46,333 patients undergoing CAG were included from 5 Chinese tertiary hospitals. SII was calculated as total peripheral platelets count × neutrophil-to-lymphocyte ratio. Patients were categorized by preprocedural SII quartiles: Q1 ≤404.5, Q2 >404.5 and ≤631.7, Q3 >631.7 and ≤1082.8, Q4 >1082.8. Univariable and multivariable logistic regression were used to reveal the link between preprocedural SII and CA-AKI., Results: A total of the 46,333 patients (62.9 ± 11.5 years, female 28.1%) were included in the study. The incidence of CA-AKI was 8.4% in Q1 group, 8.7% in Q2 group, 9.4% in Q3 group, 15.1% in Q4 group. In the multivariable model, comparing the highest (Q4 group) to lowest (Q1 group) SII level categories, preprocedural SII was related to a higher risk of CA-AKI after fully adjusting for well-known confounders, and there was no statistically difference in the other two SII level categories (Q2 and Q3 groups) compared with Q1 group (adjusted model 3: Q2 group: OR: 0.98, 95% CI: 0.87-1.11, P = 0.771; Q3 group: OR: 1.04, 95% CI: 0.92-1.18, P = 0.553; Q4: OR: 1.65, 95% CI: 1.45-1.88, p < 0.001; P for trend < 0.001). Similar results were found for all the subgroups analysis except for patients undergoing PCI, and the interaction analyses for age, PCI and AMI were significant. In addition, Kaplan-Meier curves demonstrated that the lowest quartile group showed the worst all-cause mortality in a significant SII level-dependent manner among the four groups (Log rank test; p < 0.0001)., Conclusion: Elevated preprocedural SII level was a significant and independent risk factor for CA-AKI following CAG. Higher-quality prospective studies are needed to validate the predictive value of SII for CA-AKI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial/non-financial relationships that could be construed as a potential conflict of interest., (© 2022 Lai et al.)

Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Chronic kidney disease (CKD) is very common in patients who are at a high risk of developing incident heart failure with reduced ejection fraction (HFrEF). However, the harmful effect of CKD on incident HFrEF has not yet been examined among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI)., Methods: Patients undergoing PCI with baseline left ventricular ejection fraction (LVEF) ≥ 40% were included from January 2007 to December 2018 (ClinicalTrials.gov NCT04407936). We defined incident HFrEF as a follow-up LVEF of <40% within 3-12 months after discharge. Multivariable logistical regression was performed to examine the association of CKD with incident HFrEF., Results: Overall, of 2,356 patients (mean age 62.4 ± 10.7 years, 22.2% women), 435 (18.5%) had CKD, and 83 (3.5%) developed incident HFrEF following PCI. The rate of incident HFrEF in the CKD group was higher than that in the non-CKD group (6.9 vs. 2.8%; p < 0.001). Multivariate logistic regression analysis indicated that CKD was an independent risk factor of incident HFrEF [adjusted odds ratio (aOR) = 1.75; 95% CI, 1.03-2.92; p = 0.035] after adjustment for confounders including age, gender, diabetes, hypertension, atrial fibrillation, congestive heart failure (CHF), baseline LVEF, ACEI/ARB, and statins. Furthermore, patients with incident HFrEF have a higher ratio of all-cause mortality compared to those without HFrEF (26.5 vs. 8.1%; p < 0.001)., Conclusions: Our results suggested that CKD was associated with increased risk of incident HFrEF, which was related to higher all-cause mortality in patients with CAD undergoing PCI. On this basis, more aggressive measures should be taken to prevent patients with CKD undergoing PCI from developing HFrEF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lai, Zhao, Yu, Mai, Zhou, Huang, Li, Huang, Li, Wei, Guo, Xie, Li, Lu, Liu, Chen and Liu.)

The magnetic resonance sounding (MRS) signal typically suffers from low signal-to-noise ratio (SNR). The MRS signal is severely distorted by noise, primarily harmonic and spiky noise. In terms of despiking, wavelet thresholding (WT) reconstructs the distorted content of the MRS signal, following isolation and elimination of the spiky sequence. However, WT cannot restore the MRS signal content completely when a series of spikes occurs within a given period of time. To solve this problem, a combined method of empirical mode decomposition (EMD) and WT for the removal of a series of spikes is proposed. EMD is first applied to decompose the noisy signal into several different components. The spikes that occur within a period of time are separated, the components without spikes are retained, and the components containing spiky events are selected and further processed by WT. After successively computing the wavelet coefficients of the selected components, the coefficients related to the spikes are isolated by threshold processing, and the subsequent wavelet reconstruction yields the sequence with the spikes removed. Finally, the denoised signal is obtained by adding the processed and retained components. The simulations on synthetic signals corrupted by artificial and real noise show that the proposed method improves the SNR with an accompanying improvement in the retrieval of the signal parameters. Moreover, the comparison results of the proposed and the WT methods suggest that the combined method efficiently removes a series of spikes.

Background: Apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) were identified targets for blood lipid management among coronary artery disease (CAD) patients. However, previous studies reported an inverse correlation between baseline LDL-C concentration and clinical outcomes. This study aims to explore the definite association between baseline ApoB and long-term prognosis., Methods: A total of 36,460 CAD patients admitted to Guangdong Provincial People's Hospital were enrolled and categorized into two groups: high ApoB (≥65 mg/dL) group and low ApoB (<65 mg/dL) group. The association between baseline ApoB and long-term all-cause mortality was evaluated by the Kaplan-Meier method, Cox regression analyses and restricted cubic splines., Results: The overall mortality was 12.49% ( n = 4,554) over a median follow-up period of 5.01 years. Patients with low baseline ApoB levels were paradoxically more likely to get a worse prognosis. There was no obvious difference in risk of long-term all-cause mortality when only adjusted for age, gender, and comorbidity (aHR: 1.07, 95% CI: 0.99-1.16). When CONUT and total bilirubin were adjusted, the risk of long-term all-cause mortality would reduce in the low-ApoB (<65 mg/dL) group (aHR: 0.86, 95% CI: 0.78-0.96). In the fully covariable-adjusted model, patients in the ApoB <65 mg/d group had a 10.00% lower risk of long-term all-cause mortality comparing to patients with ApoB ≥65 mg/dL (aHR: 0.90; 95% CI:0.81-0.99)., Conclusion: This study found a paradoxical association between baseline ApoB and long-term all-cause mortality. Malnutrition and bilirubin mainly mediate the ApoB paradox. Increased ApoB concentration remained linearly associated with an increased risk of long-term all-cause mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wang, Mai, Yu, Zhou, Lu, Lai, Li, Yang, Deng, Tan, Chen, Liu, Liu and Chen.)

This study aimed to investigate risk factors associated with oxaliplatin hypersensitivity reactions in cancer patients through a meta-analysis. A comprehensive retrieve of Chinese databases China National Knowledge Infrastructure, Wanfang Data, VIP Database and English databases PubMed, ScienceDirect, Embase and Cochrane library was conducted. The studies that meet the requirements for meta-analysis according to inclusion and exclusion criteria were screened and assessed for eligibility. Odds ratio (OR) / Weighted mean difference (WMD) and 95% confidence intervals (95% CIs) or calculable dichotomous and continuous raw data were extracted to perform meta-analysis using random effect model or fixed effect model on the basis of heterogeneity between studies through Review Manager 5.4 software. A total of 14 cross-sectional studies and 3367 cancer patients were included. Meta-analysis results showed that platinum exposure history (OR value 3.13, 95% CI 2.19-4.48, heterogeneity P = 0.26), allergy history (OR value 1.76, 95% CI 1.09-2.85, heterogeneity P = 0.61), platinum free interval (OR value 3.75, 95% CI 2.00-7.06, heterogeneity P = 0.83), dexamethasone premedication dose (OR value 0.28, 95% CI 0.13-0.58, heterogeneity P = 0.21) were significantly correlated to oxaliplatin hypersensitivity reactions. Gender, age, metastasis, combination with bevacizumab, XELOX regimen and cancer types were detected to have no statistically significant effect on oxaliplatin hypersensitivity reactions. Platinum exposure history, allergy history and long platinum-free interval are risk factors of oxaliplatin hypersensitivity reactions. High dexamethasone premedication dose is a protective factor of oxaliplatin hypersensitivity reactions., (© 2021. The Author(s).)

Background: The primary objective of this study aims to test patient factors, with a focus on cardiometabolic disease, influencing the performance of the Cockcroft-Gault equation in estimating glomerular filtration rate., Methods: A cohort study was performed using data from adult patients with both a 24-h urine creatinine collection and a serum creatinine available. Creatinine clearance was calculated for each patient using the Cockcroft-Gault, Modified Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations and estimates were compared to the measured 24-h urine creatinine clearance. In addition, new prediction equations were developed., Results: In the overall study population (n = 484), 44.2% of patients were obese, 44.0% had diabetes, and 30.8% had dyslipidemia. A multivariable model which incorporating patient characteristics performed the best in terms of correlation to measured 24-h urine creatinine clearance, accuracy, and error. The modified Cockcroft-Gault equation using lean body weight performed best in the overall population, the obese subgroup, and the dyslipidemia subgroup in terms of strength of correlation, mean bias, and accuracy., Conclusions: Regardless of strategy used to calculate creatinine clearance, residual error was present suggesting novel methods for estimating glomerular filtration rate are urgently needed., (© 2021. The Author(s).)

We present the fabrication of core-shell-satellite Au@SiO 2 -Pt nanostructures and demonstrate that LSPR excitation of the core Au nanoparticle can induce plasmon coupling effect to initiate photocatalytic hydrogen generation from decomposition of formic acid. Further studies suggest that the plasmon coupling effect induces a strong local electric field between the Au core and Pt nanoparticles on the SiO 2 shell, which enables creation of hot electrons on the non-plasmonic-active Pt nanoparticles to participate hydrogen evolution reaction on the Pt surface. In addition, small SiO 2 shell thickness is required in order to obtain a strong plamon coupling effect and achieve efficient photocatalytic activities for hydrogen generation., (© 2021 Wiley-VCH GmbH.)

Background: The regulatory effect of the left ventricular ejection fraction (LVEF) categories on the association of malnutrition and all-cause mortality in patients undergoing coronary angiography (CAG) have not been adequately addressed. Methods: Forty-five thousand eight hundred and twenty-six patients consecutively enrolled in the Cardiorenal ImprovemeNt (CIN) study (ClinicalTrials.gov NCT04407936) from January 2008 to July 2018 who underwent coronary angiography (CAG). The Controlling Nutritional Status (CONUT) score was applied to 45,826 CAG patients. The hazard ratios of mortality across combined LVEF and/or malnutrition categories were estimated by Cox regression models. Variables adjusted for in the Cox regression models included: age, gender, hypertension (HT), DM, PCI, coronary artery disease (CAD), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TRIG), chronic kidney disease (CKD), statins, atrial fibrillation (AF), anemia, and stroke. Population attributable risk (PAR) was estimated for eight groups stratified by nutritional status and LVEF categories. Results: In our study, 42,181(92%) of patients were LVEF ≥ 40%, of whom, 41.55 and 9.34% were in mild and moderate or severe malnutrition status, respectively, while 46.53 and 22.28% in mild and moderate or severe malnutritional status among patients with LVEF < 40%. During a median follow-up time of 4.5 years (percentile 2.8-7.1), 5,350 (11.7%) patients died. After fully adjustment, there is no difference of mortality on malnutrition in LVEF < 40% group (mild, moderate and severe vs. normal, HR (95%CI): [1.00 (0.83-0.98)], [1.20 (0.95-1.51)], [1.41 (0.87-2.29)], respectively, p for trend =0.068), but malnutrition was related to markedly increased risk of mortality in LVEF ≥ 40% group (mild, moderate, and severe vs. normal, HR (95%CI): [1.21 (1.12-1.31)], [1.56 (1.40-1.74)], and [2.20(1.67-2.90)], respectively, p for trend < 0.001, and p for interaction < 0.001). Patients with LVEF ≥ 40% had a higher malnutrition-associated risk of mortality and a higher PAR than those with LVEF < 40%. Conclusions: Malnutrition is common in CAG patients and it has a greater effect on all-cause mortality and a higher PAR in patients with LVEF ≥ 40% than LVEF < 40%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mai, Huang, Lai, Li, Wang, Huang, Shi, Yu, Hu, Liu, Zhang, Liu, Chen, Liang, Zhong and Chen.)

Background: Previous studies have shown that heart failure (HF) and chronic kidney disease (CKD) have common genetic mechanisms, overlapping pathophysiological pathways, and therapeutic drug-sodium-glucose cotransporter 2 (SGLT2) inhibitors., Methods: The genetic pleiotropy metaCCA method was applied on summary statistics data from two independent meta-analyses of GWAS comprising more than 1 million people to identify shared variants and pleiotropic effects between HF and CKD. Targets of SGLT2 inhibitors were predicted by SwissTargetPrediction and DrugBank databases. To refine all genes, we performed using versatile gene-based association study 2 (VEGAS2) and transcriptome-wide association studies (TWAS) for HF and CKD, respectively. Gene enrichment and KEGG pathway analyses were used to explore the potential functional significance of the identified genes and targets., Results: After metaCCA analysis, 4,624 SNPs and 1,745 genes were identified to be potentially pleiotropic in the univariate and multivariate SNP-multivariate phenotype analyses, respectively. 21 common genes were detected in both metaCCA and SGLT2 inhibitors' target prediction. In addition, 169 putative pleiotropic genes were identified, which met the significance threshold both in metaCCA analysis and in the VEGAS2 or TWAS analysis for at least one disease., Conclusion: We identified novel variants associated with HF and CKD using effectively incorporating information from different GWAS datasets. Our analysis may provide new insights into HF and CKD therapeutic approaches based on the pleiotropic genes, common targets, and mechanisms by integrating the metaCCA method, TWAS and VEGAS2 analyses, and target prediction of SGLT2 inhibitors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huanqiang Li et al.)

Structured abstract Aim: To elucidate the effect of miRNA (miR)-498 on autophagy and M2-like macrophage polarization in esophageal cancer. Methods: Autophagy was evaluated in esophageal cancer. Macrophage markers specific for M1- or M2-like phenotype were determined. The binding relationships between miR-498 and MDM2, MDM2 and ATF3 were analyzed. Results: miR-498 was downregulated in esophageal cancer and was associated with disease-free and overall patient survival. Enhanced miR-498 reduced LC3I conversion to LC3II and increased p62 accumulation in KYSE-150 cells, and increased macrophage polarization to M2-like phenotype in KYSE-150 and TAM co-culture. miR-498 inhibited MDM2-mediated ATF3 degradation, thus suppressing autophagy and M2-like polarization of macrophages in esophageal cancer. Conclusion: miR-498 may inhibit autophagy and M2-like polarization of macrophages to suppress esophageal cancer via MDM2/ATF3.

Background: Acute myocardial infarction (AMI), characterized by an event of myocardial necrosis, is a common cardiac emergency worldwide. However, the genetic mechanisms of AMI remain largely elusive., Methods: A genome-wide association study dataset of AMI was obtained from the CARDIoGRAMplusC4D project. A transcriptome-wide association study (TWAS) was conducted using the FUSION tool with gene expression references of the left ventricle and whole blood. Significant genes detected by TWAS were subjected to Gene Ontology (GO) enrichment analysis. Then the TWAS results of AMI were integrated with mRNA expression profiling to identify common genes and biological processes. Finally, the identified common genes were validated by RT-qPCR analysis., Results: TWAS identified 1,050 genes for the left ventricle and 1,079 genes for whole blood. Upon comparison with the mRNA expression profile, 4 common genes were detected, including HP (P TWAS = 1.22 × 10 -3 , P GEO = 4.98 × 10 -2 ); CAMP (P TWAS = 2.48 × 10 -2 , P GEO = 2.36 × 10 -5 ); TNFAIP6 (P TWAS = 1.90 × 10 -2 , P GEO = 3.46 × 10 -2 ); and ARG1 (P TWAS = 8.35 × 10 -3 , P GEO = 4.93 × 10 -2 ). Functional enrichment analysis of the genes identified by TWAS detected multiple AMI-associated biological processes, including autophagy of mitochondrion (GO: 0000422) and mitochondrion disassembly (GO: 0061726)., Conclusion: This integrative study of TWAS and mRNA expression profiling identified multiple candidate genes and biological processes for AMI. Our results may provide a fundamental clue for understanding the genetic mechanisms of AMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Liu, Li, Lun, Mai, Lai, Chen, Zhou, Yu, Yang, Chen, Chen and Liu.)

As the foremost common female malignancy, breast cancer (BC) poses a significant public health stumbling block. Although treatment protocols have improved over the years, the overall prognosis of BC remains unsatisfactory. Extensive investigations have taken place into long non coding RNAs (lncRNAs) pertaining to their involvement in carcinogenesis. The current study in connection with bioinformatics tools aimed to identify the myocardial infarction associated transcript (MIAT) as a BC-related differentially expressed lncRNA in an attempt to elucidate the effect of MIAT in BC cells. MIAT was initially overexpressed while DLG3 was down-regulated in BC. BC cells were subsequently treated with si-MIAT or/and si-DLG3, after which the expressions of DLG3 and the Hippo signaling pathway-related proteins were evaluated to analyze their regulatory mechanism in BC, which indicated that MIAT inhibition up-regulated DLG3 and activated the Hippo signaling pathway to suppress proliferation and promote apoptosis of BC cells. MS-PCR and RIP assays demonstrated that MIAT bound to the methylation proteins DNMT1, DNMT3A and DNMT3B, promoted the methylation of CpG islands in DLG3 promoter and inhibited the DLG3 expression. Moreover, our data suggested that DLG3 could bind to MST2 and regulate LAST1, which prevented the nuclear translocation of YAP. The in vitro results were further verified via the in vivo findings. Taken together, the central findings of our study demonstrate that MIAT silencing inhibits BC progression by means of up-regulating DLG3 via activation of the Hippo signaling pathway, highlighting a novel potential therapeutic target for the treatment of the BC., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC 50  = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC 50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC 50  = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC 50  = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC 50 values of 0.16, 0.27, and 0.19 μM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC 50  = 3.32 μM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A class of 3-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were designed, synthesized and evaluated for their in vitro biological activities against maternal embryonic leucine zipper kinase (MELK). Among these derivatives, the optimized compound 16h exhibited potent enzyme inhibition (IC 50  = 32 nM) and excellent anti-proliferative effect with IC 50 values from 0.109 μM to 0.245 μM on A549, MDA-MB-231 and MCF-7 cell lines. The results of flow cytometry indicated that 16h promoted apoptosis of A549 cells in a dose-dependent manner and effectively arrested A549 cells in the G0/G1 phase. Further investigation indicated that compound 16h potently suppressed the migration of A549 cells, had moderate stability in rat liver microsomes and showed moderate inhibitory activity against various subtypes of human cytochrome P450. However, compound 16h is a multi-target kinase inhibitor and recently several studies reported MELK expression is not required for cancer growth, suggesting that compound 16h suppressed the proliferation and migration of cancer cells should through an off-target mechanism. Collectively, compound 16h has the potential to serve as a new lead compound for further anticancer drug discovery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Transgenic mouse are reliable, convenient models for studying human hepatocellular carcinoma (HCC). The development of a synthetically engineered Sleeping Beauty (SB) transposon system further enables the viral-free, efficient delivery of desired oncogenes to mouse tissues. Here, we describe an SB transposon-based approach to induce HCC in mice by expressing a hyperactive form of N-RAS, N-RAS G12V , while silencing the endogenous Trp53 gene via hydrodynamic tail vein injection, a method to rapidly deliver naked plasmids to mouse liver.

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC 50 values in the 10 -8 -10 -9  M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC 50  = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC 50  = 3.2 μM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

FeP as a noble-metal-free catalyst has been successfully decorated onto the Zn x Cd 1-x S photocatalyst surface through an in situ phosphating process. In particular, the 2 % FeP/Zn 0.5 Cd 0.5 S-P sample showed the best hydrogen generation activity of 24.45 mmol h -1  g -1 which is over 130 times higher than that of pure Zn 0.5 Cd 0.5 S and nearly 1.3 times higher than that of the 1 % Pt-loaded Zn 0.5 Cd 0.5 S-P sample. The apparent quantum yield (AQY) of the 2 % FeP/Zn 0.5 Cd 0.5 S-P was estimated to be over 10 % at wavelengths up to 470 nm. The fluorescence spectra and electrochemical measurement results suggest that the decorated FeP not only reduces the overpotential for H 2 evolution but also promotes the separation of the photogenerated charge carriers through formation of a heterojunction with Zn 0.5 Cd 0.5 S, which eventually leads to the superior activity of the FeP/Zn 0.5 Cd 0.5 S-P photocatalyst for visible-light-driven hydrogen generation., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

It is crucial to dynamically analyze the movement of neutrophils (a type of white cell) during the process of inflammation. However, manually tracking and analyzing the cells is a time-consuming task due to the large volume of cells and similar appearance. To facilitate neutrophils analysis and address the issues mentioned above, we propose to leverage high-order temporal information as a cue to track neutrophils. A tensor-based approach is introduced to encode the high-order motion pattern and appearance variation for multi-frame multicell association. To evaluate the proposed method, we collected 354 sequences of cells from 200 frames of microscopic images. We conduct a systematic study on the collected data and show significant performance improvement over other solutions.

LC resonance magnetic sensors are widely used in low-field nuclear magnetic resonance (LF-NMR) and surface nuclear magnetic resonance (SNMR) due to their high sensitivity, low cost and simple design. In magnetically shielded rooms, LC resonance magnetic sensors can exhibit sensitivities at the fT/&radic;Hz level in the kHz range. However, since the equivalent magnetic field noise of this type of sensor is greatly affected by the environment, weak signals are often submerged in practical applications, resulting in relatively low signal-to-noise ratios (SNRs). To determine why noise increases in unshielded environments, we analysed the noise levels of an LC resonance magnetic sensor ( L &ne; 0) and a Hall sensor ( L &asymp; 0) in different environments. The experiments and simulations indicated that the superposed ringing of the LC resonance magnetic sensors led to the observed increase in white noise level caused by environmental interference. Nevertheless, ringing is an inherent characteristic of LC resonance magnetic sensors. It cannot be eliminated when environmental interference exists. In response to this problem, we proposed a method that uses matching resistors with various values to adjust the quality factor Q of the LC resonance magnetic sensor in different measurement environments to obtain the best sensitivity. The LF-NMR experiment in the laboratory showed that the SNR is improved significantly when the LC resonance magnetic sensor with the best sensitivity is selected for signal acquisition in the light of the test environment. (When the matching resistance is 10 k&Omega;, the SNR is 3.46 times that of 510 &Omega;). This study improves LC resonance magnetic sensors for nuclear magnetic resonance (NMR) detection in a variety of environments.

Background & Aims: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors., Methods: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice., Results: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21., Conclusions: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents., (Copyright © 2018. Published by Elsevier Inc.)