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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. [ABSTRACT FROM AUTHOR]

Recent publications have uncovered a largely overlooked role of RNA splicing factors and alternative splicing (AS) decisions in controlling liver adaptation, physiology, and homeostasis. Dynamic regulation of pre-mRNA splicing and AS allows for expanded complexity of gene expression in liver increasing its capacity for adaptation in response to metabolic stimuli. The mechanistic complexity required for pre-mRNA splicing, involving multiple cis and trans elements, creates a liability underlying human disease which is especially obvious in a multifunctional organ such as liver. Increased understanding of liver splicing plasticity is enabling the development of isoform-specific or splicing factor-targeted therapeutics. 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. [ABSTRACT FROM AUTHOR]

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 log10CKMB (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 log10NT‐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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: FeP as a noble‐metal‐free catalyst has been successfully decorated onto the ZnxCd1−xS photocatalyst surface through an in situ phosphating process. In particular, the 2 % FeP/Zn0.5Cd0.5S−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 Zn0.5Cd0.5S and nearly 1.3 times higher than that of the 1 % Pt‐loaded Zn0.5Cd0.5S−P sample. The apparent quantum yield (AQY) of the 2 % FeP/Zn0.5Cd0.5S−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 H2 evolution but also promotes the separation of the photogenerated charge carriers through formation of a heterojunction with Zn0.5Cd0.5S, which eventually leads to the superior activity of the FeP/Zn0.5Cd0.5S−P photocatalyst for visible‐light‐driven hydrogen generation. [ABSTRACT FROM AUTHOR]

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%, χ2 test (P<0.05 vs. CM-IRI) and 35%, χ2 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. [ABSTRACT FROM AUTHOR]

• Compared with PAC-UF, severer fouling occurred with biochar-UF without GAC. • PAC uniformly dispersed on membranes, while biochar tended to agglomerate. • RGAC exhibited optimal fouling reduction performance with lowest energy consumption. • Substantial amounts of small-sized PC were released by two cylindrical-shaped GACs. • RGAC-biochar-UF achieved commensurate effluent quality but better permeability. 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 Ca2+ 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Magnetic resonance sounding (MRS) signals are often severely distorted by noise, primarily the power-line harmonics which originates from anthropogenic interferences. Noise cancellation is a particularly important issue for the application of the MRS method. In order to reduce the harmonic peaks as well as the noise floor between the 50 Hz harmonics effectively, a method based on the wavelet modulus maximum is proposed. The method is based on marking the local modulus maximum points in the wavelet transform coefficients and removed the modulus maximum contributed by noise for MRS signal reconstruction. The optimum wavelet basis for noise cancelling is determined through simulations with synthetic signals. The accuracy and stability of the proposed method are investigated using synthetic signals embedded in both artificial and field-recorded noise. In addition, the results of the test on field data show the proposed method can effectively improve the fitting accuracy of the signal parameters and obtain stable inversion results. • The WMM method can suppress the harmonic peaks and noise floor effectively. • The WMM method can improve the efficiency by processing one measurement signal. • The noise cancellation method can suggest for other geophysical signal processing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • GAC and PAC were integrated with UF process for enhancing system performance. • Fluidized GAC was effective in removing fouling formed by both PAC and feed water. • PAC improved UF permeate quality mainly by absorbing humic-acid like substances. • Such GAC-PAC-UF process proposed was energy efficient without damages to membranes. Ultrafiltration (UF) has been extensively employed in current water treatment practice, during which limited removal for soluble contaminants and membrane fouling remain two perennial hurdles to efficient operation. This study proposed a promising approach by simultaneous coupling of fluidized granular activated carbon (GAC) and PAC with UF process, whereby PAC was responsible for improving effluent quality, and fluidized GAC was targeted for mitigating UF fouling and PAC deposition. The operational performance of such integrated GAC-PAC-UF system was systemically evaluated in a lab-scale setup. The results showed that fluidized GAC particles with larger size appeared highly effective in removing PAC deposition and fouling formed by surface water. PAC addition improved the effluent quality mainly by adsorbing humic acid-like substances. More importantly, energy consumption by GAC fluidization was found to be at least an order-of-magnitude lower than conventional fouling control methods employed in UF. Furthermore, redundancy analysis revealed that the key mechanism for UF fouling mitigation was tied to GAC particle momentum, whereas inorganic fouling mitigation was mostly achieved by GAC-induced liquid turbulence. It is expected that such integrated GAC-PAC-UF process proposed should be technically feasible and economically viable, potentially achieving high permeate quality and reducing membrane fouling with limited energy requirement. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. Image 1 • A series of thieno[3,2- d pyrimidine derivatives were designed and synthesized. • Most compounds suppressed the enzymatic activities of FAK with IC 50 values of 10−7–10−8 M. • 26f displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells. • 26f promoted apoptosis and suppressed the migration of MDA-MB-231 cells. • 26f arrested MDA-MB-231 cells in the G0/G1 phase. [ABSTRACT FROM AUTHOR]

We present the fabrication of core‐shell‐satellite Au@SiO2‐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 SiO2 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 SiO2 shell thickness is required in order to obtain a strong plamon coupling effect and achieve efficient photocatalytic activities for hydrogen generation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The boom of microelectronic devices and their diverse applications has heightened the demand for innovative and effective energy supply strategies. The longevity of contemporary microelectronic devices predominantly depends on direct human intervention power supply methods, encompassing battery replacement or recharging. However, these methods may falter in specific scenarios, such as when facing liquid conditions in vivo. Here, a concept of swimmable micro‐batteries (MBs) for targeted power delivery is presented. This is achieved through the design of a flexible polydimethylsiloxane/Fe3O4 soft‐magnetic substrate for actuation, polydimethylsiloxane/neodymium‐iron‐boron (NdFeB) hard‐magnetic tabs for precise targeting, and quasi‐solid‐state Zn//MnO2 battery for power generation. These swimmable MBs exhibit an impressive areal capacity of 102.3 µAh cm‐2, remarkable waterproofing, adjustable output voltage or capacity, rapid response, and accurate remote magnetic field manipulation, enabling targeted power supply available. This novel swimmable MB design broadens the function of MBs and may open a new avenue for their future development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Membrane separation technology has been generally preferred for treating high-salinity organic wastewater during the last decades of years. Despite not suitable for ion removal, ultrafiltration (UF) is quite appropriate and widely employed for retaining solids, organic matters and macromolecules etc. from high-salinity wastewater. However, limited efforts have been made to investigate the UF fouling characteristics affected by such high saline environment. In this study, sodium chloride (NaCl) with the concentration higher than 10 g/L was employed to examine its impacts on the UF fouling behaviors. The results showed that the involvement of high-concentration NaCl remarkably aggravated HA fouling formation, whereas mitigated BSA fouling development. In the presence of NaCl, HA seemed to form a more homogenous fouling layer, while substantial scattered and large NaCl crystals with different shapes appeared on BSA fouling layer. Further analysis demonstrated that NaCl at high levels induced the agglomeration of BSA foulants, leading to their slower transportation to membrane surface and alleviated the formation of cake layer. Comparatively, the electrostatic attraction and thermodynamic interactions between HA-HA and HA-membrane were substantially increased at high-salinity condition, probably facilitating HA migration to membrane and enhancing fouling layer development. Consequently, the different effects of high salinity on HA and BSA fouling were systematically revealed with their formation mechanisms proposed, which should provide an insightful guidance for membrane fouling control when high-salinity organic wastewater is treated with membrane-based technique. [Display omitted] • High-salinity environment enhanced HA fouling, while reduced BSA fouling formation. • Substantial NaCl crystals with different shapes appeared on BSA cake layer. • Fouling mechanisms of HA and BSA under the effects of high salinity were proposed. • This study offers new insight into UF fouling when treating high saline wastewater. [ABSTRACT FROM AUTHOR]

Despite great recent advances in visual tracking, its further development, including both algorithm design and evaluation, is limited due to lack of dedicated large-scale benchmarks. To address this problem, we present LaSOT, a high-quality Large-scale Single Object Tracking benchmark. LaSOT contains a diverse selection of 85 object classes, and offers 1550 totaling more than 3.87 million frames. Each video frame is carefully and manually annotated with a bounding box. This makes LaSOT, to our knowledge, the largest densely annotated tracking benchmark. Our goal in releasing LaSOT is to provide a dedicated high quality platform for both training and evaluation of trackers. The average video length of LaSOT is around 2500 frames, where each video contains various challenge factors that exist in real world video footage,such as the targets disappearing and re-appearing. These longer video lengths allow for the assessment of long-term trackers. To take advantage of the close connection between visual appearance and natural language, we provide language specification for each video in LaSOT. We believe such additions will allow for future research to use linguistic features to improve tracking. Two protocols, full-overlap and one-shot, are designated for flexible assessment of trackers. We extensively evaluate 48 baseline trackers on LaSOT with in-depth analysis, and results reveal that there still exists significant room for improvement. The complete benchmark, tracking results as well as analysis are available at http://vision.cs.stonybrook.edu/~lasot/. [ABSTRACT FROM AUTHOR]

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. • MIAT is abundantly expressed while DLG3 is down-regulated in breast cancer. • DLG3 is a target gene of MIAT. • MIAT activates the Hippo signaling pathway by promoting methylation of DLG3 promoter. [ABSTRACT FROM AUTHOR]

• A library of 2,4-disubstituted-7 H -pyrrolo[2,3- d pyrimidine derivatives were designed and synthesized. • Most compounds suppressed the enzymatic activities of FAK with IC 50 values of 10−8–10−9 M. • 18h exhibited potent enzyme inhibition against FAK (IC 50 = 19.1 nM). • 18h potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cell lines. • 18h induced apoptosis and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. 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-7 H -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. [ABSTRACT FROM AUTHOR]

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/√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 ≠ 0) and a Hall sensor (L ≈ 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 kΩ, the SNR is 3.46 times that of 510 Ω). This study improves LC resonance magnetic sensors for nuclear magnetic resonance (NMR) detection in a variety of environments. [ABSTRACT FROM AUTHOR]

Yibo He, Hongyu Lu, and Yihang Ling contributed equally to this work and share first authorship. Correction: Prediabetes and all-cause mortality in young patients undergoing coronary artery angiography: a multicenter cohort study in China The study sponsor/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.". [Extracted from the article]

We have prepared Pd-loaded plasmonic WO 3− x nanowires with retained strong plasmon absorption in the visible and NIR region, and demonstrated that the plasmon excitation of WO 3− x nanowires by long wavelength irradiation can greatly promote Suzuki coupling reactions catalyzed by the attached Pd nanoparticles in terms of the main product yield and selectivity, which is attributed to the photothermal effect with strong localized plasmon heating on the WO 3− x nanowire surface. Our studies reveal that the contributions of plasmon excitation can not only affect the reactions directly involving the plasmonic structure itself, but also assist the reactions catalyzed by the third-part materials attached on the plasmonic structure surface. [ABSTRACT FROM AUTHOR]

Triangular Ag-Pd alloy nanoframes were successfully synthesized through galvanic replacement by using Ag nanoprisms as sacrificial templates. The ridge thickness of the Ag-Pd alloy nanoframes could be readily tuned by adjusting the amount of the Pd source during the reaction. These obtained triangular Ag-Pd alloy nanoframes exhibit superior electrocatalytic activity for the methanol oxidation reaction as compared with the commercial Pd/C catalyst due to the alloyed Ag-Pd composition as well as the hollow-framed structures. This work would be highly impactful in the rational design of future bimetallic alloy nanostructures with high catalytic activity for fuel cell systems. [ABSTRACT FROM AUTHOR]

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 Δ adcA Δ adcAII 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, Δ adcA Δ adcAII 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. • The expressions of adcA and AadcAII are upregulated in response to Zn limitation. • AdcA and AdcAII have overlapping functionality in zinc acquisition in S. suis. • Simultaneous deletion of AdcA and AdcAII attenuates S. suis virulence in mice. • The expressions of adcA and adcAII are negatively regulated by AdcR in S. suis. [ABSTRACT FROM AUTHOR]

• A library of 1 H -pyrrolo[2,3- b ]pyridine derivatives were designed and synthesized. • 16h exhibited potent enzyme inhibition against MELK (IC 50 = 32 nM). • 16h potently inhibited the proliferation of A549, MDA-MB-231 and MCF-7 cell lines. • 16h is a multi-target kinase inhibitor when tested on a panel of 50 kinases. • 16h induced apoptosis and suppressed the migration of A549 cells. A class of 3-substituted 1 H -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. [ABSTRACT FROM AUTHOR]

A series of 7 H -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 μ M) 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. Image 1 • A series of 7 H -pyrrolo[2,3- d pyrimidine derivatives were designed and synthesized. • The compounds suppressed the enzymatic activities of FAK with IC 50 values of 10−8–10−9 M. • The compounds inhibited the proliferation of MDA-MB-231 and A549 cells. • 25b exhibited potent enzyme inhibition (IC 50 = 5.4 nM) and good selectivity. • 25b possessed good microsomal metabolic stability in vitro. [ABSTRACT FROM AUTHOR]

Triangular Ag – Pd alloy nanoframes can be synthesized through galvanic replacement by using Ag nanoprisms as sacrificial templates. The obtained triangular Ag – Pd alloy nanoframes exhibit superior electrocatalytic activity for methanol oxidation compared with the commercial Pd/C catalyst owing to the alloyed Ag – Pd composition as well as the hollow ‐ framed structures. This work could have a high impact on the rational design of future bimetallic alloy nanostructures with high catalytic activity for fuel cell systems. For more details see the Communication by L. Xu, C. Xue, et al. on page 8691 ff. [ABSTRACT FROM AUTHOR]