Association of genetic variations of 3'-UTR in clopidogrel pharmacokinetic-relevant genes with clopidogrel response in Han Chinese patients with coronary artery disease.

Dual antiplatelet therapy with aspirin and clopidogrel has reduced ischemic vascular events significantly. Genetics influence, especially those in clopidogrel pharmacokinetic-relevant genes partially accounts for interindividual pharmacodynamic variability of clopidogrel. However, most studies have concentrated on the genetic variations in introns, exons, or promoters of the candidate genes, and the association between genetic variations in 3'-UTR in clopidogrel pharmacokinetic-relevant genes and clopidogrel response is unknown. In our study, ten different algorithms were applied to pick potential miRNAs targeting the clopidogrel pharmacokinetic-relevant genes. Furthermore, the correlation between miRNA expression profiles and mRNA expression of corresponding clopidogrel pharmacokinetic-relevant genes were analyzed. Through comprehensive analysis, including bioinformatics prediction and correlation analysis of miRNA and mRNA expression profiles, miR-218-5p and miR-506-5p were supposed to regulate the expression of PON1 via binding with its 3'-UTR. Moreover, PON1 rs854551 and rs854552 were located in miRNA recognizing sequences and may serve as potential miRSNPs possibly affecting PON1 expression. The rs854552 polymorphism was genotyped and platelet reactivity index (PRI) indicative of clopidogrel response was measured in 341 Chinese coronary artery disease (CAD) patients 24h after administration of 300 mg clopidogrel. Our results showed that PON1 rs854552 had a significant influence on PRI in CAD patients, especially in patients with CYP2C19 extensive metabolic phenotype. In conclusion, PON1 rs854552 polymorphisms may affect clopidogrel response. Bioinformatics prediction followed by functional validation could aid in decoding the contribution of unexplained variations in the 3'-UTR in drug-metabolizing enzymes on clopidogrel response.

Customizing Cerium Oxide Particle Synthesis with Hybrid Polyion Complex Templates for Enhanced Oxidation Performance in Photo-Fenton Processes.

Hybrid poly-ion complexes were synthesized through the complexation of a double hydrophilic copolymer with Ce(III) ions. These colloids act as reservoirs for cerium ions, enabling the synthesis of cerium-based Prussian blue nanoparticles with a cubic structure, a narrow size distribution around 100 nm, and good colloidal stability in water. Upon high-temperature calcination, these nanoparticles are transformed into a cerium/iron-based metal oxide catalyst (CeO2/Fe2O3). The resultant composite catalyst demonstrates superior performance in the photo-Fenton oxidation of methylene blue pollutants, achieving a conversion efficiency that rivals other metal-based oxides and cerium-based catalysts.

Autologous CIK cells combined with chemotherapy as the first-line treatment for locally advanced or metastatic gastric cancer is safe and feasible.

Aim: To evaluate the safety and initial efficacy of autologous cytokine-induced killer (CIK) cells combined with S-1+oxaliplatin (SOX) as the first-line treatment for locally advanced or metastatic gastric cancer (GC). Materials and methods: In this two-arm, single-center exploratory trial, patients with locally advanced or metastatic GC were randomly assigned (1:1) to receive autologous CIK cells in combination with SOX (CIK-SOX) or SOX alone. The primary endpoint was the incidence of adverse events (AEs). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) served as the secondary endpoints. Results: Fifty-nine patients were enrolled in the study between November 20, 2014 and September 6, 2017. A total of 31 patients received CIK-SOX and 28 patients received SOX. The most common AEs in both groups were gastrointestinal reaction, leucopenia, neutropenia, anemia, thrombocytopenia, hyperbilirubinemia, and elevated aspartate transaminase concentration, with a higher incidence of these conditions in the SOX group. The median PFS for the CIK-SOX and SOX groups was 6.9 and 4.9 months, respectively (hazard ratio (HR) 0.80, p=0.45). The respective median OS values were 17.8 and 9.75 months (HR 0.76, p=0.34). Patients who received more than three injections of specific lymphocyte subsets benefited the most from this combination therapy. Cox univariate and multivariate analyses showed that tumor metastasis to more than two organs was the main risk factor for PFS and OS. A total of 29 patients in the CIK-SOX group and 25 in the SOX group had measurable lesions. The ORR for the CIK-SOX and SOX groups was 55.2% and 32.0%, while the DCR was 93.1% and 88.0%, respectively. Conclusion: The safety of CIK-SOX as the first-line treatment for patients with locally advanced or metastatic GC was good. Although the PFS and OS in the CIK-SOX group were not statistically significantly different compared to the values in the SOX alone group, this treatment increased the PFS and OS duration, with the absolute improvement in OS of about 8.05 months. Continuous benefit from the CIK-SOX treatment was observed during long-term follow-up. Clinical trial registration: https://clinicaltrials.gov/study/NCT02504229?term=NCT02504229&rank=1, identifier ChiCTR-IPR-15005923; NCT02504229.

Driving safety zone model oriented motion planning framework for autonomous truck platooning.

A driving-safety-zone-model-oriented motion planning framework (DSZMF) is proposed for autonomous platoons in heterogeneous driving environments with complex driving behaviors and interactions between human-driven and autonomous vehicles. As an extension of the responsibility-sensitive-safety (RSS) model, the driving safety zone model ensures that autonomous truck platoons adhere to explicit and implicit traffic rules as rational traffic participants. It consists of three zones created by safe distances and artificial potential field (APF), namely the restricted zone, the coordinated zone, and pre-cautionary zone. The Rational Traffic Participant (RTP) module is created by using a Finite State Machine (FSM) to provide an optimized platooning behavioral strategy based on the dynamic states of surrounding vehicles. Furthermore, the distributed model predictive controllers are utilized for motion planning, while the H infinity controller is developed to maintain the string stability of the autonomous platoon. The proposed DSZMF generates behavioral decisions by thoroughly considering the driving safety zone model, string stability, and multiple vehicle dynamics constraints. Finally, three critical scenarios are co-simulated for case studies, and the simulation results demonstrate that the DSZMF improves the safe time integration rate over the existing MCF by 18.9%, 11.1%, and 11.6% in three scenarios, respectively. In addition, DSZMF increases the minimum longitudinal and lateral Time to Collision (TTC) values to reduce collision risks. The case studies validate the efficacy of the proposed method for safety assurance and collaborative control of the autonomous platoon.

Gut microbiota might mediate the benefits of high-fiber/acetate diet to cardiac hypertrophy mice.

Continuously prolonged cardiac hypertrophy results in maladaptive myocardial remodeling, which affects cardiac function and can eventually lead to heart failure. Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, have been reported to be associated with cardiovascular diseases (CVD). Gut microbiota may mediate between dietary fiber and SCFA effects on cardiac hypertrophy. The mice model of isoproterenol (ISO)-induced cardiac hypertrophy was constructed and verified for physiological, functional, and fibrotic alterations in this study. Both high-fiber and acetate diet improved physiological indexes, ameliorated cardiac functions, and relieved fibrotic alterations in model mice hearts; collectively, cardiac hypertrophy in mice receiving both high-fiber and acetate diet improved. Following 16s rDNA sequencing and integrative bioinformatics, analyses indicated that both high-fiber and acetate diet caused alterations in mice gut microbiota compared with the ISO group, including OTU composition and abundance. In conclusion, high-fiber and acetate diet improve the physiological status, cardiac functions, and fibrotic alterations in ISO-induced hypertrophic mice. Besides, considering the alterations in mice gut microbiota in response to single ISO, both high-fiber and acetate diet treatment, gut microbiota might mediate the favorable benefits of both high-fiber and acetate diet on cardiac hypertrophy.

Clinical effectiveness and efficiency of a new steerable sheath technology for radiofrequency ablation in Chinese patients with atrial fibrillation: a retrospective comparative cohort study.

Background: The clinical effectiveness and efficiency of a steerable sheath for radiofrequency catheter ablation (RFCA) in Chinese patients with atrial fibrillation (AF) needs to be compared with a fixed curve sheath to optimize RFCA procedure. Methods: This retrospective study included adult AF patients with their first RFCA that was conducted by the same electrophysiologist using a steerable sheath (VIZIGO, Biosense Webster, Inc.) or a fixed curve sheath (NaviEase, Synaptic Medical) in a Chinese tertiary care hospital from January to November 2021. The medical records kept at the hospital were the source of study data that included patient baseline characteristics and outcome measures for the clinical effectiveness and efficiency of RFCA procedure. Multivariate generalized linear regression analyses were performed to explore the impact of sheath type on clinical effectiveness and efficiency after adjustment. Results: Fourteen patients using steerable sheath and 34 patients using fixed curve sheath for RFCA were included in the data analysis. Most of patient baseline characteristics associated with the two study groups were comparable except that the steerable sheath group had significantly higher left atrium diameter (41.9±6.5 vs. 38.1±3.9 mm, P=0.017) and larger left atrium volume (150.4±29.5 vs. 126.8±27.5 mL, P=0.017) than the fixed curve sheath group. Using steerable sheath was associated with significantly shorter total pulmonary vein isolation (PVI) fluoroscopy time and post-surgery hospital length of stay (LOS) than using fixed curve sheath in both unadjusted comparisons (PVI fluoroscopy time: 1.3±1.5 vs. 4.0±3.9 min, P=0.004; post-surgery LOS: 2.1±0.7 vs. 2.9±1.5 days, P=0.034) and multivariate generalized regression analyses (PVI fluoroscopy time: coefficient =-0.859, P=0.014; post-surgery LOS: coefficient =-0.303, P=0.018). Conclusions: Compared to fixed curve sheath, steerable sheath used for RFAC could have the potential to shorten the PVI fluoroscopy time and reduce post-surgery LOS in a Chinese real-world hospital setting. Future real-world studies with large sample size are needed to confirm our study findings.

Iron-based hybrid polyionic complexes as chemical reservoirs for the pH-triggered synthesis of Prussian blue nanoparticles.

HYPOTHESIS: Hybrid polyion complexes (HPICs) obtained from the complexation in aqueous solution of a double hydrophilic block copolymer and metal ions can act as efficient precursors for the controlled synthesis of nanoparticles. In particular, the possibility to control the availability of metal ions by playing on the pH conditions is of special interest to obtain nanoparticles with controlled size and composition. EXPERIMENTS: HPICs based on Fe3+ ions were used to initiate the formation of Prussian blue (PB) nanoparticles in presence of potassium ferrocyanide in reaction media with varying pH values. FINDINGS: Complexed Fe3+ ions within HPICs can be easily released by adjusting the pH value either through the addition of a base/acid or by using a merocyanine photoacid. This allows to modulate the reactivity of Fe3+ ions with potassium ferrocyanide present in solution. As a result, PB nanoparticles with different structures (core, core-shell), composition and controlled size are obtained.

ERAP1 Shows Distinct Regulatory Mechanisms on Blood Pressure Modulation Between Males and Females.

The authors have withdrawn their manuscript owing to editing error. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Decreased platelet miR-199a-5p level might lead to high on-clopidogrel platelet reactivity in patients with coronary artery disease.

Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. This study aimed to investigate the association between platelet miRNA levels and clopidogrel efficacy. Here we recruited 508 CAD patients who underwent clopidogrel antiplatelet therapy and determined the platelet reactivity index (PRI) to evaluate antiplatelet reactivity responses to clopidogrel. Subsequently, 22 patients with extreme clopidogrel response were selected for platelet small RNA sequencing. Another 41 CAD patients taking clopidogrel were collected to verify the differentially expressed candidate miRNAs. We found the metabolic types of the CYP2C19 enzyme (based on CYP2C19 * 2 and * 3 polymorphisms) could significantly affect the PRI of CAD patients with or without percutaneous coronary intervention (PCI) in Chinese. A total of 43 miRNAs were differentially expressed in the platelets from the 22 extreme clopidogrel response samples, and 109 miRNAs were differentially expressed in the 13 CYP2C19 extensive metabolizers with extreme clopidogrel response. Platelet miR-199a-5p levels were correlated negatively with PRI after clopidogrel therapy. Studies in cultured cells revealed that miR-199a-5p inhibited the expression of VASP, a key effector protein downstream of the P2Y12 receptor. In conclusion, we found the expression of VASP could be inhibited by miR-199a-5p, and decreased platelet miR-199a-5p was associated with high on-clopidogrel platelet reactivity in CAD patients.

What is the context?● Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment.● Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy.● Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway.What is new?● We found that decreased platelet miR-199a-5p level was associated with high on-clopidogrel platelet reactivity.● Overexpression of miR-199a-5p significantly down-regulated the expression of VASP protein in cultured cells.What is the impact?● The current study provided new insights into the exploration of interindividual variability in clopidogrel response from the perspective of miR-199a-5p and VASP interaction.

A Randomized Clinical Trial of Transgender Women Switching to B/F/TAF: The (mo)BETTA Trial.

Background: Cardiometabolic disease in transgender women (TW) is affected by gender-affirming hormonal therapies (GAHTs), HIV, and antiretroviral therapy (ART). We evaluated the 48-week safety/tolerability of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs continued ART in TW on GAHT. Methods: TW on GAHT and suppressive ART were randomized 1:1 to switch to B/F/TAF (Arm A) or continue current ART (Arm B). Cardiometabolic biomarkers, sex hormones, bone mineral density (BMD) and lean/fat mass by DXA scan, and hepatic fat (controlled continuation parameter [CAP]) were measured. Wilcoxon rank-sum/signed-rank and χ2 tests compared continuous and categorical variables. Results: TW (Arm A n = 12, Arm B n = 9) had a median age of 45 years. Ninety-five percent were non-White; 70% were on elvitegravir or dolutegravir, 57% TAF, 24% abacavir, and 19% TDF; 29% had hypertension, 5% diabetes, and 62% dyslipidemia. There were no adverse events. Arm A/B had 91%/89% undetectable HIV-1 RNA at week 48 (w48). Baseline (BL) osteopenia (Arm A/B 42%/25%) and osteoporosis (17%/13%) were common, without significant changes. BL lean/fat mass were similar. At w48, Arm A had stable lean mass but increased limb (3 lbs) and trunk (3 lbs) fat (within-arm P < .05); fat in Arm B remained stable. No changes occurred in lipid or glucose profiles. Arm B had a greater w48 decrease (-25 vs -3 dB/m; P = .03) in CAP. BL and w48 concentrations of all biomarkers were similar. Conclusions: In this cohort of TW, switch to B/F/TAF was safe and metabolically neutral, though greater fat gain occurred on B/F/TAF. Further study is needed to better understand cardiometabolic disease burden in TW with HIV.

CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome.

Background: Dual antiplatelet therapy with clopidogrel and aspirin is the primary treatment for patients who undergo percutaneous coronary intervention. However, the interindividual difference in clopidogrel response is remarkable, and high on-treatment platelet reactivity (HTPR) can increase the risk of thrombotic events after percutaneous coronary intervention. Objective: We studied novel accessible factors that possibly affect clopidogrel response in DNA methylation. Methods: Methylation 850K bead chips were used to detect DNA methylation levels. The platelet reactivity index (PRI) was determined in 330 subjects with acute coronary syndrome (ACS) after administration of clopidogrel 300 mg loading dose or at least 5 days of 75 mg daily maintenance dose. Results: Overall, 32 discovery samples showed extreme clopidogrel response: 16 with HTPR (PRI > 75%) and 16 with non-HTPR (PRI < 26%). Overall, 61 differential methylation loci (DMLs) were observed between the 2 groups. Most were in the open sea and intergenic regions in the genome. In the validation stage, HTPR showed a lower level of CD80_cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the CD80_cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, P = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, P = .01) and decreased CD80_cg06300880 methylation (P < .0001). Multivariate regression analysis showed that both CYP2C19 poor metabolizers and CD80_rs34394661 AA (P = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, CD80_cg06300880 methylation (P = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS. Conclusion: CD80_cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.

Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8, and Their Binding Proteins, Follistatin and Follistatin-Like Protein-3, With Measures of Skeletal Muscle Mass, Muscle Strength, and Physical Function in Older Adults.

BACKGROUND: Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. METHODS: Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). RESULTS: GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. CONCLUSIONS: GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength.

Reference intervals for free testosterone in adult men measured using a standardized equilibrium dialysis procedure.

BACKGROUND: Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories. OBJECTIVE: To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma. FT in dialysate was measured using a CDC-certified liquid chromatography tandem mass spectrometry assay. RESULTS: In healthy nonobese men, the 2.5th, 10th, 50th, 90th, and 97.5th percentile values for FT were 66, 91, 141, 240, and 309 pg/ml, respectively; corresponding values for men, 19-39 years, were 120, 128, 190, 274, and 368 pg/ml, respectively. FT levels by age groups exhibit the expected age-related decline. FT levels were negatively associated with body mass index, age, and sex hormone-binding globulin (SHBG) levels. Percent FT was lower in middle-aged and older men than young men adjusting for SHBG level. DISCUSSION: Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions. CONCLUSION: Reference intervals for free FT levels (normative range 66-309 pg/ml [229-1072 pmol/L] in all men and 120-368 pg/ml [415-1274 pmol/L] in men, 19-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials.

The Effect of Teach-Back Combined with King Interactive Standard Mode on the Life of COPD Patients.

Background: COPD is a common clinical chronic airway inflammatory disease that occurs mostly in middle-aged and older adults over the age of 40. The incidence of COPD is increasing year by year and the onset of age is gradually becoming younger. Objective: To observe the effect of teach-back combined with king interaction on the life of patients with chronic obstructive pulmonary disease (COPD). Methods: A total of 100 COPD patients admitted to our hospital from Jan 2021 to Jan 2022 were retrospectively selected to be divided into 50 cases in the control group and 50 cases in the observation group according to the nursing methods. The control group was treated with routine nursing intervention, while the observation group was treated with teach-back combined with king interactive standard mode intervention. The differences in Self-Care Ability Assessment Scale (ESCA) score, St. George's Respiratory Questionnaire (SGRQ) score, Mental State Assessment Scale (MSSNS) score, 6-minute walking distance (6MWD), and pulmonary function indexes were compared between the two groups before and after the intervention. The success rate and patient compliance of each index in the groups were also recorded. Results: After 3 months and 6 months of intervention, the total SGRO score and its factor scores of self-care skills, self-care responsibility, self-concept, health knowledge level in them were all higher than those before the intervention, while the total SGRO score and its factor scores of respiratory symptoms, activity limitation, disease influence, and so on were all decreased compared with those before the intervention. The ESCA score of the observation group was significantly higher than that of the control one after 3 months and 6 months of intervention, while the SGRQ score was significantly lower than that of the control one, with statistical significance (P < 0.05). After 3 months of intervention, the total score of MSSNS and the scores of anxiety, depression, loneliness, and other factors in both groups were decreased compared with those before intervention. After 6 months of intervention, the total score of MSSNS and scores of each factor in both groups were decreased compared with those before intervention, and the MSSNS scores in the observation group were significantly lower than those in the control group after the intervention, which was statistically significant (P < 0.05). After 3 months and 6 months of intervention, 6MWD, forced vital capacity (FVC), forced expiratory value in 1 second (FEV1), and FVC/FEV1 in them were all higher than those before intervention, and 6MWD and pulmonary function were significantly higher in the observation group than in the control group after 3 and 6 months of intervention, which was statistically significant (P < 0.05). The ESCA score, SGRQ score, MSSNS score, pulmonary function compliance rate, and compliance rate in the observation group were significantly higher than those in the control group, which was statistically significant (P < 0.05). Conclusion: The use of teach-back combined with king interactive standard mode in COPD patients can improve the patient's self-care ability, reduce psychological negative emotions, and improve the quality of life.

Pharmacogenomics in drug-induced cardiotoxicity: Current status and the future.

Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT.

Ectopic Acsl6 Overexpression Partially Improves Isoproterenol-Induced Cardiac Hypertrophy In Vivo and Cardiomyocyte Hypertrophy In Vitro.

ABSTRACT: The increase in cardiac myocyte size is a critical issue in cardiac hypertrophy development. In this study, 61 differentially expressed genes between hypertrophic rats and normal controls were enriched in the positive modulation of fatty acid uptake, fatty acid metabolism and degradation, cardiac conduction, and the oxidation of carbohydrates and other processes. Acsl6 was significantly downregulated in hypertrophic rat and mouse hearts according to online data. Based on the experimental data, Acsl6 was underexpressed in ISO-induced cardiac hypertrophy mouse model and isoproterenol (ISO)-induced cardiomyocyte hypertrophy cell model. In vivo, Acsl6 overexpression partially attenuated ISO-induced increases in the cross-sectional area and cardiac hypertrophy, elevated hypertrophic markers, and caused impairment of cardiac function. In vitro, Acsl6 overexpression partially attenuated ISO-induced cardiomyocyte hypertrophy and increased hypertrophic markers. Conclusively, Ascl6 is downregulated in ISO-induced cardiac hypertrophy mouse model and ISO-induced cardiomyocyte hypertrophy cell model. Acsl6 overexpression could partially improve cardiac hypertrophy in vivo and cardiomyocyte hypertrophy in vitro, possibly through the regulation of HIF-1α/Hippo pathway.

Flexible thermoelectrics based on ductile semiconductors.

Flexible thermoelectrics provide a different solution for developing portable and sustainable flexible power supplies. The discovery of silver sulfide-based ductile semiconductors has driven a shift in the potential for flexible thermoelectrics, but the lack of good p-type ductile thermoelectric materials has restricted the reality of fabricating conventional cross-plane π-shaped flexible devices. We report a series of high-performance p-type ductile thermoelectric materials based on the composition-performance phase diagram in AgCu(Se,S,Te) pseudoternary solid solutions, with high figure-of-merit values (0.45 at 300 kelvin and 0.68 at 340 kelvin) compared with other flexible thermoelectric materials. We further demonstrate thin and flexible π-shaped devices with a maximum normalized power density that reaches 30 µW cm-2 K-2. This output is promising for the use of flexible thermoelectrics in wearable electronics.

Methyltransferase-like 3 promotes the progression of lung cancer via activating PI3K/AKT/mTOR pathway.

Methyltransferase-like 3 (METTL3) catalyses N6-methyladenosine (m6 A) modification on messenger RNA (mRNA) and participates in a wide range of biological functions via epigenetically regulating gene expression. Recent studies suggested that dysregulation of METTL3 is associated with multiple human cancers; however, the role of METTL3 in lung cancer remains unclear. In the present study, through transcriptome analysis of lung cancer patients, we found that METTL3 is overexpressed in lung cancer patients and is associated with poor patient survival. More importantly, combining both in vitro and in vivo models, we revealed that in lung cancer cells, METTL3 overexpression activates PI3K/AKT/mTOR pathway and mTOR-mediated protein synthesis. Mechanistically, METTL3 promotes PI3K expression by introducing m6 A modification in PI3K 3' untranslated region (3' UTR). Elevated PI3K level then activates downstream AKT and mTOR signalling pathway and results in rapid cancer cell proliferation and metastasis. Taken together, our study reveals that METTL3-mediated m6 A methylation promotes lung cancer progression via activating PI3K/AKT/mTOR pathway.

Accurate Measurement and Harmonized Reference Ranges for Total and Free Testosterone Levels.

Diagnosing testosterone deficiency requires accurate and precise measurement of total testosterone levels by an accurate method, such as liquid chromatography-tandem mass spectrometry in a laboratory certified by an accuracy-based program (eg, Centers for Disease Control and Prevention's Hormone Standardization (HoST) Program), and, if needed, free testosterone level. Free testosterone level should ideally be measured by equilibrium dialysis method. Testosterone levels should be measured in 2 or more fasting samples obtained in the morning. Harmonized reference ranges for total testosterone can be applied to laboratories that certified by the HoST Program.