Recent advances in age-related metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 25% of the world's population and has become a leading cause of chronic liver disease. In recent years, an increasing amount of data suggests that MASLD is associated with aging. As the population ages, age-related MASLD will become a major global health problem. Targeting an aging will become a new approach to the treatment of MASLD. This paper reviews the current studies on the role of aging-related factors and therapeutic targets in MASLD, including: Oxidative stress, autophagy, mitochondrial homeostasis, bile acid metabolism homeostasis, and dysbiosis. The aim is to identify effective therapeutic targets for age-related MASLD and its progression.

[Spatiotemporal Occurrence of Organophosphate Esters in the Surface Water and Sediment of Taihu Lake and Relevant Risk Assessment].

Aiming to explore the spatiotemporal occurrence of organophosphate esters (OPEs) in the aquatic environment of Taihu Lake and to assess the relevant ecological risk, monomeric and oligomeric OPEs in the surface water and sediment of Taihu Lake were determined using solid phase extraction and ultra-high performance liquid chromatography-tandem mass spectrometry. The target monomeric OPEs included chlorinated OPEs, alkyl OPEs, and aryl OPEs. There was no significant difference in the spatial distribution of OPEs in water and sediment between the pollutant-impacted and less-impacted zones. The average concentrations of OPEs in summer and winter were, respectively, 752.7 and 498.5 ng·L-1 in water and 124.0 and 54.5 ng·g-1 in sediment, indicating an obvious seasonal difference, especially for the monomeric OPEs. The OPEs levels in both the water and sediment were ranked in the order of chlorinated OPEs > alkyl OPEs > aryl OPEs≈oligomeric OPEs. The pseudo-partitioning coefficients (Kd) of OPEs between the sediment and surface water of Taihu Lake were much higher in summer (0.05-4.17 L·g-1) compared to those in winter (0.02-3.47 L·g-1) and were significantly positively correlated with the lg Kow values of OPEs. Based on the median concentrations of OPEs in the water of Taihu Lake, the ecological risk of OPEs was assessed by risk quotient (RQ) values, which indicated a medium risk at an RQ level of 0.34 during winter and 0.35 during summer. The assessment results showed that the risk ranking of OPEs was consistent with that of their concentrations, and the monomeric OPEs posed a higher ecological risk in summer compared to that in winter. Although the ecological risk of oligomeric OPEs in this study was not serious and was lower than that of monomeric OPEs, it is an urgent requirement to conduct ecotoxicology studies on oligomeric OPEs in the future since available data is highly limited at present.

Integrated Anionic Zirconium-Organic Cage and Cationic Boron-Imidazolate Cage for Synergetic Optical Limiting.

Making oppositely charged metal-organic cages (MOCs) into a tightly ordered structure may bring interesting functions. Herein, we report a novel structure composed of anionic (Zr4 L6 )8- (L=embonate) tetrahedral cages and in situ-formed cationic [Zn4 (Bim)4 ]4+ (Bim=[BH(im)3 ]- ; im=imidazole) cubic cages. Chiral transfer is observed from enantiopure (Zr4 L6 )8- cage to enantiopure [Zn4 (Bim)4 ]4+ cage. A pair of enantiomers (PTC-373(Δ) and PTC-373(Λ)) are formed. PTC-373 exhibits high chemical and thermal stabilities, affording an interesting single-crystal-to-single-crystal transformation. More importantly, the combination of ionic pair cages significantly enhances its third-order nonlinear optical property, and its thin-film exhibits an excellent optical limiting effect.

Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver ischemia-reperfusion model.

BACKGROUND: Mesenchymal stem cells (MSCs) have been used in liver transplantation and have certain effects in alleviating liver ischemia-reperfusion injury (IRI) and regulating immune rejection. However, some studies have indicated that the effects of MSCs are not very significant. Therefore, approaches that enable MSCs to exert significant and stable therapeutic effects are worth further study. AIM: To enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in the mouse liver ischemia-reperfusion (I/R) model via interferon-γ (IFN-γ) priming. METHODS: Apoptosis was analyzed by flow cytometry to evaluate the safety of IFN-γ priming, and indoleamine 2,3-dioxygenase (IDO) levels were measured by quantitative real-time reverse transcription polymerase chain reaction, western blotting, and ELISA to evaluate the efficacy of IFN-γ priming. In vivo, the liver I/R model was established in male C57/BL mice, hematoxylin and eosin and TUNEL staining was performed and serum liver enzyme levels were measured to assess the degree of liver injury, and regulatory T cell (Treg) numbers in spleens were determined by flow cytometry to assess immune tolerance potential. Metabolomics analysis was conducted to elucidate the potential mechanism underlying the regulatory effects of primed MenSCs. In vitro, we established a hypoxia/reoxygenation (H/R) model and analyzed apoptosis by flow cytometry to investigate the mechanism through which primed MenSCs inhibit apoptosis. Transmission electron microscopy, western blotting, and immunofluorescence were used to analyze autophagy levels. RESULTS: IFN-γ-primed MenSCs secreted higher levels of IDO, attenuated liver injury, and increased Treg numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced autophagy in the mouse livers. In the H/R model, autophagy inhibitors increased the level of H/R-induced apoptosis, indicating that autophagy exerted protective effects. In addition, primed MenSCs decreased the level of H/R-induced apoptosis via IDO and autophagy. Further rescue experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway. CONCLUSION: IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model by secreting higher IDO levels. MenSCs and IDO activated the AMPK-mTOR-autophagy axis to reduce IRI, and IDO increased Treg numbers in the spleen and enhanced the MenSC-mediated induction of immune tolerance. Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future.

Abnormal presentation of pregnancy and postpartum initial-onset systemic lupus erythematosus combined with diffuse alveolar hemorrhage: A case report.

Systemic lupus erythematosus (SLE) is an autoimmune disease that most commonly occurs in women of childbearing age. However, cases of SLE with abnormal pregnancy as the initial manifestation, involving the development of diffuse alveolar hemorrhage (DAH), have rarely been reported. Herein, we report the case of a young woman who underwent a cesarean section for fetal distress and growth restriction at 35 + 1 weeks' gestation. Following discharge, she experienced progressive worsening of anemia and chest tightness, which was later diagnosed as SLE complicated by DAH.

Negative life events and aggression among Chinese rural left-behind adolescents: do self-esteem and resilience mediate the relationship?

BACKGROUND: Left-behind adolescents (LBAs) are adolescents aged 11-18 years who are separated from their parents and left behind in local cities by one or both parents for a period of more than 6 months. LBAs in rural areas are likely to engage in aggressive behavior, which can affect interpersonal relationships, reduce academic performance, and even lead to anxiety and depression. To our knowledge, no studies have examined the mediating effect of resilience and self-esteem on the relationship between negative life events and aggression among Chinese rural LBAs. Therefore, this study aimed to explore the relationship between negative life events and aggression among Chinese rural LBAs and how self-esteem and resilience mediate the association. METHODS: Using a stratified random sampling method, 1344 LBAs in Hunan Province of China were investigated. Information was collected by a self-designed sociodemographic questionnaire, Adolescent Self-Rating Life Events Checklist, Resilience Scale Chinese Adolescent, Rosenberg Self-Esteem Scale and Aggression Scales to assess the psychology of LBAs. Data analysis was conducted using descriptive statistics, Pearson correlation, and regression analysis to estimate direct and indirect effects using bootstrap analysis. RESULTS: Negative life events were significantly related to self-esteem (r = - 0.338), resilience (r = - 0.359), and aggression (r = 0.441). Aggression was directly affected by self-esteem (ß = - 0.44) and resilience (ß = - 0.34). Negative life events were not only directly related to aggression (ß = 0.34, 95% CI: 0.275 ~ 0.398) but also showed an indirect effect on aggression through self-esteem and resilience. The direct effect, total effect and indirect effect of negative life events on aggression through self-esteem and resilience were 0.3364, 0.4344 and 0.0980, respectively. The mediating effect of self-esteem and resilience accounted for 22.56% of the relationship between negative life events and aggression. CONCLUSIONS: We found that self-esteem and resilience mediated most negative life events on aggression. It is imperative for educators and families to improve LBAs' self-esteem and resilience to reduce the occurrence of aggression. Future intervention studies should be designed to strengthen self-esteem and resilience.

Practical synthesis of isocoumarins via Rh(III)-catalyzed C-H activation/annulation cascade.

Herein, we report an unprecedented Rh(III)-catalyzed C-H activation/annulation cascade of readily available enaminones with iodonium ylides towards the convenient synthesis of isocoumarins. This coupling system proceeds in useful chemical yields (up to 93%) via a cascade C-H activation, Rh-carbenoid migratory insertion and acid-promoted intramolecular annulation. The success of gram-scale reaction and diverse functionalization of isocoumarins demonstrated the synthetic utility of this protocol.

Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway.

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-generated metabolite, elicits thrombotic events by enhancing platelet reactivity; however, no studies have reported the effects of TMAO on the metabolism of and response to clopidogrel. OBJECTIVES: To determine whether choline and TMAO could significantly impair metabolic activation of and platelet response to clopidogrel in choline- or TMAO-fed mice and the mechanisms involved. METHODS: Male mice were fed with vehicle control (Ctrl), TMAO, choline alone or in combination with 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 for 14 days and then treated with Ctrl or a single oral dose of clopidogrel. Plasma TMAO, protein levels of clopidogrel-metabolizing enzymes in the liver, plasma concentrations of clopidogrel and its metabolites, and adenosine diphosphate-induced platelet aggregation and activation were measured. In addition, HepG2 cells were treated with Ctrl or TMAO alone or in combination with N-acetyl-L-cysteine, ML385, or apocynin, and CES1, reactive oxygen species (ROS), and Nrf2 protein levels were measured, respectively. RESULTS: TMAO significantly increased Ces1 protein expression and activity and clopidogrel hydrolysis in the liver as well as intracellular ROS and CES1 levels and Nrf2 nucleus translocation in HepG2 cells but decreased the formation of clopidogrel active metabolite and impaired platelet response to clopidogrel. Furthermore, concomitant use of 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 effectively reversed choline- or TMAO-induced impairment of inhibition of platelet aggregation by clopidogrel in mice, respectively. CONCLUSIONS: Choline and TMAO impair the metabolic activation of and platelet response to clopidogrel through the activation of the NOX-dependent ROS/Nrf2/CES1 pathway, suggesting novel strategies for overcoming clopidogrel resistance from bench to bedside.

Identification of tumor-specific neoantigens and immune clusters of hepatocellular carcinoma for mRNA vaccine development.

BACKGROUND: To screen efficacious neoantigens for the development of LIHC mRNA vaccines, construct LIHC immune clusters, and therefore select patients who might benefit from vaccination. METHODS: RNA-seq data and clinical information of 371 TCGA-LIHC and 231 ICGC-LIHC cohorts were downloaded. Differentially expressed genes and their associations with prognosis were analyzed by GEPIA, genetic alterations were examined in the cBioPortal portal, and the association between genes and immune infiltrating cells was explored by TIMER. The immune clusters were constructed by consistency clustering, and the immune landscape was described using CIBERSORT. RESULTS: POLR3C and KPNA2 were identified as LIHC tumor neoantigens related to inferior prognosis and antigen-presenting cell infiltration. In addition, three immune clusters (IC1, IC2 and IC3) with significant differences in molecular, immune cytological, and clinical features were identified in both the TCGA and ICGC LIHC cohorts. Immune "hot" phenotype IC3 displayed a better survival than IC2, and immune "cold" phenotype IC1 exhibited a high tumor mutation burden. CONCLUSION: In conclusion, for the development of anti-LIHC mRNA vaccines, we identified efficacious neoantigens POLR3C and KPNA2, profiled the tumor microenvironment of LIHC, and identified IC1 patients as the subgroup who might not most benefit from vaccination.

Improved Insulating Properties of Polymer Dielectric by Constructing Interfacial Composite Coatings.

Polymeric dielectrics exhibit remarkable dielectric characteristics and wide applicability, rendering them extensively employed within the domain of electrical insulation. Nevertheless, the electrical strength has always been a bottleneck, preventing its further utilization. Nanocomposite materials can effectively improve insulation strength, but uniform doping of nanofillers in engineering applications is a challenge. Consequently, a nanocomposite interfacial coating was meticulously designed to interpose between the electrode and the polymer, which can significantly improve DC breakdown performance. Subsequently, the effects of filler concentration and coating duration on DC breakdown performance, high field conductivity, and trap distribution characteristics were analyzed. The results indicate that the composite coating introduces deep traps between the electrode-polymer interface, which enhances the carrier confinement, resulting in reduced conductivity and enhanced DC breakdown strength. The incorporation of a composite coating at the interface between the electrode and polymer presents novel avenues for enhancing the dielectric insulation of polymers.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. AIM: In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. METHODS: MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. RESULTS: In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). CONCLUSION: The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

Genomics and morphometrics reveal the adaptive evolution of pikas.

Pikas (Lagomorpha: Ochotonidae) are small mouse-like lagomorphs. To investigate their adaptation to different ecological environments during their dispersal from the Qinghai-Xizang (Tibet) Plateau (QTP), we collected 226 pikas and measured 20 morphological characteristics and recorded habitat information. We also sequenced the genome of 81 specimens, representing 27 putative pika species. The genome-wide tree based on 4 090 coding genes identified five subgenera, i.e., Alienauroa, Conothoa, Lagotona, Ochotona, and Pika, consistent with morphometric data. Morphologically, Alienauroa and Ochotona had similar traits, including smaller size and earlier divergence time compared to other pikas. Consistently, the habitats of Alienauroa and Ochotona differed from those of the remaining subgenera. Phylogenetic signal analysis detected 83 genes significantly related to morphological characteristics, including several visual and hearing-related genes. Analysis of shared amino acid substitutions and positively selected genes (PSGs) in Alienauroa and Ochotona identified two genes, i.e., mitochondrial function-related TSFM (p.Q155E) and low-light visual sensitivity-related PROM1 (p.H419Y). Functional experiments demonstrated that TSFM-155E significantly enhanced mitochondrial function compared to TSFM-155Q in other pikas, and PROM1-419Y decreased the modeling of dynamic intracellular chloride efflux upon calcium uptake. Alienauroa and Ochotona individuals mostly inhabit different environments (e.g., subtropical forests) than other pikas, suggesting that a shift from the larger ancestral type and changes in sensory acuity and energy enhancement may have been required in their new environments. This study increases our understanding of the evolutionary history of pikas.

Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice.

BACKGROUND AND PURPOSE: Overweight or obese patients exhibit poorer platelet responses to clopidogrel. However, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to discover whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high-fat diet-induced obese mice. EXPERIMENTAL APPROACH: A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high-fat diet-induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP-induced platelet activation and aggregation, the expression of genes involved in the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocytes in bone marrow. The relevant genes and potential signalling pathways were predicted and enriched according to the GEO datasets available from obese patients. KEY RESULTS: Obese patients exhibited significantly attenuated antiplatelet effects of clopidogrel. In diet-induced obese mice, systemic exposure of clopidogrel active metabolite H4 was reduced but that of its hydrolytic metabolite was increased due to down-regulation of certain P450s but up-regulation of carboxylesterase-1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed. CONCLUSION AND IMPLICATIONS: Obesity attenuated metabolic activation of clopidogrel and increased counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients.

Smart Textiles Based on MoS2 Hollow Nanospheres for Personal Thermal Management.

Two-dimensional transition metal dichalcogenides are of particular interest in high-performance photothermal conversion, yet there remains a huge challenge in their practical application in smart textiles for healthcare, energy, and personal protection. Herein, we controllably prepared MoS2 hollow nanospheres with a high photothermal conversion efficiency of 36% via a microemulsion-hydrothermal method, which was further applied to construct photothermal fibers for personal thermal management after a hot-blast dip-drying process. Because of the prominent photothermal effect, the temperature of the photothermal fibers sharply increases from the room temperature value of 25.0 to 55.5 °C in 60 s under near-infrared illumination with a power density of 500 W/cm2. Furthermore, the photothermal fiber pad demonstrated an obvious temperature enhancement of 38.0 °C from a skin temperature of 22.0 °C after it was irradiated by natural sunlight for 60 s. Significantly, the antibacterial elimination rates of the photothermal fibers for Escherichia coli and Staphylococcus aureus are ∼99.9 and ∼99.8%, respectively. This strategy affords an avenue toward the practical application of photothermal materials in smart fibers for personal thermoregulation.

Morphological and phylogenetic evidence for recognition of two new species of Hyphoderma (Basidiomycota) from southern China, with a key to all Chinese Hyphoderma.

Wood-inhabiting fungi play crucial roles as decomposers in forest ecosystems and, in this study, two new wood-inhabiting corticioid fungi, Hyphodermapuerense and H.tenuissimum spp. nov., are proposed, based on a combination of morphological features and molecular evidence. Hyphodermapuerense is characterised by effused basidiomata with smooth to floccose hymenial surface, a monomitic hyphal system with clamped generative hyphae and ellipsoid basidiospores. Hyphodermatenuissimum is characterised by resupinate basidiomata with tuberculate to minutely-grandinioid hymenial surface, septate cystidia and cylindrical to allantoid basidiospores. Sequences of ITS and nLSU rRNA markers of the studied samples were generated and phylogenetic analyses were performed with Maximum Likelihood, maximum parsimony and Bayesian Inference methods. These analyses showed that the two new species clustered into Hyphoderma, in which H.puerense grouped with H.moniliforme and H.tenuissimum formed a singleton lineage. In addition, an identification key to Chinese Hyphoderma is provided.

Deficiency of TRIM32 Impairs Motor Function and Purkinje Cells in Mid-Aged Mice.

Proper functioning of the cerebellum is crucial to motor balance and coordination in adult mammals. Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, play essential roles in cerebellar motor function. Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase that is involved in balance activities of neurogenesis in the subventricular zone of the mammalian brain and in the development of many nervous system diseases, such as Alzheimer's disease, autism spectrum disorder, attention deficit hyperactivity disorder. However, the role of TRIM32 in cerebellar motor function has never been examined. In this study we found that motor balance and coordination of mid-aged TRIM32 deficient mice were poorer than those of wild-type littermates. Immunohistochemical staining was performed to assess cerebella morphology and TRIM32 expression in PCs. Golgi staining showed that the extent of dendritic arborization and dendritic spine density of PCs were decreased in the absence of TRIM32. The loss of TRIM32 was also associated with a decrease in the number of synapses between parallel fibers and PCs, and in synapses between climbing fibers and PCs. In addition, deficiency of TRIM32 decreased Type I inositol 1,4,5-trisphosphate 5-phosphatase (INPP5A) levels in cerebellum. Overall, this study is the first to elucidate a role of TRIM32 in cerebellar motor function and a possible mechanism, thereby highlighting the importance of TRIM32 in the cerebellum.

Proposal of a new T-stage classification system for ampullary carcinoma based on Surveillance, Epidemiology and End Result (SEER) database.

BACKGROUND: Tumor size is still considered a useful prognostic factor in currently available tumor-node-metastasis (TNM) classification staging systems for most solid tumors, but the significance of tumor size on the prognosis of ampullary carcinoma remains controversial. The aim of the current study was to propose a new T-stage classification system for ampullary carcinoma to address the impact of tumor size on the prognostic outcome. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 1080 patients with ampullary carcinoma who underwent radical surgical resection between 2004 and 2015. Based on the results obtained from analysis of various clinicopathologic factors, a new T-stage classification system was proposed. RESULTS: Among the 1080 patients, 618 were men and 462 were women, with a median tumor size of 2.3 (range 0.1-12) cm. Using the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual, we noticed significant differences in overall survival (OS) between T2 vs. T3 tumors (P < 0.001) and T3 vs. T4 tumors (P = 0.002), but failed to observe significant differences between T1 vs. T2 tumors (P = 0.498) in our pair-wise comparison. Using the newly developed T-stage classification system, we were able to differentiate significant differences in OS between T1 vs. T2 tumors (P = 0.032), T2 vs. T3 tumors (P < 0.001) and T3 vs. T4 tumor (P = 0.003) in all pair-wise comparisons. The c-index of the new staging system was 0.653 (95% CI: 0.629-0.677), showing a better discriminatory power than the 0.636 of the 7th AJCC staging system (95% CI: 0.612-0.660). CONCLUSIONS: The new T-stage classification system described herein can better differentiate prognostic outcomes after radical resection in patients with ampullary carcinoma by incorporating tumor size and depth of tumor infiltration.

Short-term standard alcohol consumption enhances platelet response to clopidogrel through inhibition of Nrf2/Ces1 pathway and induction of Cyp2c in mice.

AIMS: Drinking alcohol is prevalent worldwide; however, it is unknown whether alcohol could affect the antiplatelet effects of clopidogrel in patients when taking both concomitantly. This study was designed to investigate the influence of short-term standard alcohol consumption on the metabolic activation of and platelet response to clopidogrel in mice as well as the mechanisms involved. MAIN METHODS: Male C57BL/6J mice were administered with normal saline (vehicle control) or alcohol at 2 g/kg/day for 7 days, and then gavaged with vehicle control or a single dose of clopidogrel at 10 mg/kg. Inhibition of ADP-induced platelet aggregation and activation by clopidogrel, plasma concentrations of clopidogrel and its active metabolite H4, and changes in mRNA and protein expression of genes related to clopidogrel metabolism and its regulation were measured in mice pretreated with or without alcohol. KEY FINDINGS: Compared with vehicle control, alcohol pretreatment significantly reduced hydrolysis of clopidogrel as a result of significant down-regulation of Nrf2-mediated Ces1 expression (responsible for the formation of clopidogrel carboxylate), increased metabolic activation of clopidogrel due to significant up-regulation of Cyp2c (for the formation of active thiol metabolite H4), and consequently enhanced inhibition of ADP-induced platelet aggregation and activation by clopidogrel. SIGNIFICANCE: Short-term standard alcohol consumption would significantly enhance suppression of ADP-induced platelet aggregation and activation by clopidogrel through significant inhibition of Nrf2/Ces1 signaling pathway and induction of Cyp2c, suggesting that alcohol may interact with drugs that are predominantly metabolized by CES1 or CYP2C in patient care, including clopidogrel.

Single-pixel imaging with neutrons.

Neutron imaging is an invaluable tool for noninvasive analysis in many fields. However, neutron facilities are expensive and inconvenient to access, while portable sources are not strong enough to form even a static image within an acceptable time frame using traditional neutron imaging. Here we demonstrate a new scheme for single-pixel neutron imaging of real objects, with spatial and spectral resolutions of 100 µm and 0.4% at 1 Å, respectively. Low illumination down to 1000 neutron counts per frame pattern was achieved. The experimental setup is simple, inexpensive, and especially suitable for low intensity portable sources, which should greatly benefit applications in biology, material science, and industry.