TSHR signaling promotes hippocampal dependent memory formation through modulating Wnt5a/ß-catenin mediated neurogenesis.

Subclinical hyperthyroidism is defined biochemically as a low or undetectable thyroid-stimulating hormone (TSH) with normal thyroid hormone levels. Low TSHR signaling is considered to associate with cognitive impairment. However, the underlying molecular mechanism by which TSHR signaling modulates memory is poorly understood. In this study, we found that Tshr-deficient in the hippocampal neurons impairs the learning and memory abilities of mice, accompanying by a decline in the number of newborn neurons. Notably, Tshr ablation in the hippocampus decreases the expression of Wnt5a, thereby inactivating the ß-catenin signaling pathway to reduce the neurogenesis. Conversely, activating of the Wnt/ß-catenin pathway by the agonist SKL2001 results in an increase in hippocampal neurogenesis, resulting in the amelioration in the deficits of memory caused by Tshr deletion. Understanding how TSHR signaling in the hippocampus regulates memory provides insights into subclinical hyperthyroidism affecting cognitive function and will suggest ways to rationally design interventions for neurocognitive disorders.

Association Between Monocyte-to-High-Density Lipoprotein Ratio and Prediabetes: A Cross-Sectional Study in Chinese Population.

Background: The monocyte-to-high-density lipoprotein cholesterol (MHR) ratio has been linked to metabolic disorders. However, there is limited research on the predisposition to MHR and prediabetes. Hence, we conducted a study to investigate the relationship between MHR and the prevalence of prediabetes. Methods: In total, 85,293 participants were included in our cross-sectional observational study. Multivariable regression analysis, subgroup analyses, and interaction testing were used to determine the relationship between MHR and prediabetes. To explore the non-linear association of MHR with prediabetes risk, generalized additive model (GAM) and smoothing splines were applied. The threshold effect analysis of MHR on the risk of prediabetes was further employed to identify the turning point. Results: After controlling for covariates, the results indicated that a positive correlation persisted between MHR and prediabetes (odds ratio (OR) =1.64, 95% confidence interval (CI), 1.48-1.82), and subgroup analyses found a more robust correlation between MHR and prediabetes in individuals with lower age, SBP, DBP, TG, TC and higher values of BMI and LDL-C than in their counterparts. Additionally, the correlation between MHR and the risk of prediabetes was found to be non-linear, with a turning point of -0.4 (Log-Likelihood Ratio, P< 0.001). The impact of variables on the two sides of the turning point were 1.94 (1.72, 2.19) and 0.88 (0.69, 1.14). Conclusion: The positive correlation between MHR and the risk of prediabetes in Chinese participants was observed to be non-linear, and MHR ≤ -0.4 was strongly positively correlated with prediabetes risk.

Fast measurement of coherence-orbital angular momentum matrices of random light beams using off-axis holography and coordinate transformation.

We propose an effective protocol to measure the coherence-orbital angular momentum (COAM) matrix of an arbitrary partially coherent beam. The method is based on an off-axis holography scheme and the Cartesian-polar coordinate transformation, which enables to simultaneously deal with all the COAM matrix elements of interest. The working principle is presented and discussed in detail. A proof-of-principle experiment is carried out to reconstruct the COAM matrices of partially coherent beams with spatially uniform and non-uniform coherence states. We find an excellent agreement between the experimental results and the theoretical predictions. In addition, we show that the OAM spectrum of a partially coherent beam can also be directly acquired from the measured COAM matrix.

The impact of type 2 diabetes mellitus on the clinical profile, myocardial fibrosis, and prognosis in non-ischemic dilated cardiomyopathy: a prospective cohort study.

BACKGROUND: The impact of the coexistence of type 2 diabetes mellitus (T2DM) in patients with non-ischemic dilated cardiomyopathy (DCM) on clinical profiles, myocardial fibrosis, and outcomes remain incompletely understood. METHOD: A total of 1152 patients diagnosed with non-ischemic DCM were prospectively enrolled from June 2012 to October 2021 and categorized into T2DM and non-T2DM groups. Clinical characteristics, cardiac function, and myocardial fibrosis evaluated by CMR were compared between the two groups. The primary endpoint included both all-cause mortality and heart transplantation. Cause of mortality was classified into heart failure death, sudden cardiac death, and non-cardiac death. Cox regression analysis and Kaplan-Meier analysis were performed to identify the association between T2DM and clinical outcomes. Propensity score matching (PSM) cohort including 438 patients was analyzed to reduce the bias from confounding covariates. RESULTS: Among the 1152 included DCM patients, 155 (13%) patients had T2DM. Patients with T2DM were older (55 ± 12 vs. 47 ± 14 years, P < 0.001), had higher New York Heart Association (NYHA) functional class (P = 0.003), higher prevalence of hypertension (37% vs. 21%, P < 0.001), atrial fibrillation (31% vs. 16%, P < 0.001), lower left ventricular (LV) ejection fraction (EF) (23 ± 9% vs. 27 ± 12%, P < 0.001), higher late gadolinium enhancement (LGE) presence (55% vs. 45%, P = 0.02), and significantly elevated native T1 (1323 ± 81ms vs. 1305 ± 73ms, P = 0.01) and extracellular volume fraction (ECV) (32.7 ± 6.3% vs. 31.3 ± 5.9%, P = 0.01) values. After a median follow-up of 38 months (interquartile range: 20-57 months), 239 patients reached primary endpoint. Kaplan-Meier analysis showed that patients with T2DM had worse clinical outcomes compared with those without T2DM in the overall cohort (annual events rate: 10.2% vs. 5.7%, P < 0.001). T2DM was independently associated with an increased risk of primary endpoint in the overall (Hazard ratio [HR]: 1.61, 95% CI: 1.13-2.33, P = 0.01) and PSM (HR: 1.54, 95% CI: 1.05-2.24, P = 0.02) cohorts. Furthermore, T2DM was associated with a higher risk of heart failure death (P = 0.006) and non-cardiac death (P = 0.02), but not sudden cardiac death (P = 0.16). CONCLUSIONS: Patients with T2DM represented a more severe clinical profile and experienced more adverse outcomes compared to those without T2DM in a large DCM cohort. TRIAL REGISTRATION: Trial registration number: ChiCTR1800017058; URL: https://www. CLINICALTRIALS: gov .

Prognostic value of mid-term cardiovascular magnetic resonance follow-up in patients with non-ischemic dilated cardiomyopathy: a prospective cohort study.

BACKGROUND: The prognostic value of follow-up cardiovascular magnetic resonance (CMR) in dilated cardiomyopathy (DCM) patients is unclear. We aimed to investigate the prognostic value of cardiac function, structure, and tissue characteristics at mid-term CMR follow-up. METHODS: The study population was a prospectively enrolled cohort of DCM patients who underwent guideline-directed medical therapy with baseline and follow-up CMR, which included measurement of biventricular volume and ejection fraction, late gadolinium enhancement, native T1, native T2, and extracellular volume. During follow-up, major adverse cardiac events (MACE) were defined as a composite endpoint of cardiovascular death, heart transplantation, and heart-failure readmission. RESULTS: Among 235 DCM patients (median CMR interval: 15.3 months; interquartile range: 12.5-19.2 months), 54 (23.0%) experienced MACE during follow-up (median: 31.2 months; interquartile range: 20.8-50.0 months). In multivariable Cox regression, follow-up CMR models showed significantly superior predictive value than baseline CMR models. Stepwise multivariate Cox regression showed that follow-up left ventricular ejection fraction (LVEF; hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.91-0.96; p < 0.001) and native T1 (HR, 1.01; 95% CI, 1.00-1.01; p = 0.030) were independent predictors of MACE. Follow-up LVEF ≥ 40% or stable LVEF < 40% with T1 ≤ 1273 ms indicated low risk (annual event rate < 4%), while stable LVEF < 40% and T1 > 1273 ms or LVEF < 40% with deterioration indicated high risk (annual event rate > 15%). CONCLUSIONS: Follow-up CMR provided better risk stratification than baseline CMR. Improvements in the LVEF and T1 mapping are associated with a lower risk of MACE.

Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death.

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Role of the In-Situ-Formed Surface (Pt-S-O)-Ti Active Structure in SO2-Promoted C3H8 Combustion over a Pt/TiO2 Catalyst.

Typically, SO2 unavoidably deactivates catalysts in most heterogeneous catalytic oxidations. However, for Pt-based catalysts, SO2 exhibits an extraordinary boosting effect in propane catalytic oxidation, but the promotive mechanism remains contentious. In this study, an in situ-formed tactful (Pt-S-O)-Ti structure was concluded to be a key factor for Pt/TiO2 catalysts with a substantial SO2 tolerance ability. The experiments and theoretical calculations confirm that the high degree of hybridization and orbital coupling between Pt 5d and S 3p orbitals enable more charge transfer from Pt to S species, thus forming the (Pt-S-O)-Ti structure with the oxygen atom dissociated from the chemisorbed O2 adsorbed on oxygen vacancies. The active oxygen atom in the (Pt-S-O)-Ti active structure is a robust site for C3H8 adsorption, leading to a better C3H8 combustion performance. This work can provide insights into the rational design of chemical bonds for high SO2 tolerance catalysts, thereby improving economic and environmental benefits.

Liver T1 Mapping Derived From Cardiac Magnetic Resonance Imaging: A Potential Prognostic Marker in Idiopathic Dilated Cardiomyopathy.

BACKGROUND: Hepatic alterations are common aftereffects of heart failure (HF) and ventricular dysfunction. The prognostic value of liver injury markers derived from cardiac MRI studies in nonischemic dilated cardiomyopathy (DCM) patients is unclear. PURPOSE: Evaluate the prognostic performance of liver injury markers derived from cardiac MRI studies in DCM patients. STUDY TYPE: Prospective. POPULATION: Three hundred fifty-six consecutive DCM patients diagnosed according to ESC guidelines (age 48.7 ± 14.2 years, males 72.6%). FIELD STRENGTH/SEQUENCE: Steady-state free precession, modified Look-Locker inversion recovery T1 mapping and phase sensitive inversion recovery late gadolinium enhancement (LGE) sequences at 3 T. ASSESSMENT: Clinical characteristics, conventional MRI parameters (ventricular volumes, function, mass), native myocardial and liver T1, liver extracellular volume (ECV), and myocardial LGE presence were assessed. Patients were followed up for a median duration of 48.3 months (interquartile range 42.0-69.9 months). Primary endpoints included HF death, sudden cardiac death, heart transplantation, and HF readmission; secondary endpoints included HF death, sudden cardiac death, and heart transplantation. Models were developed to predict endpoints and the incremental value of including liver parameters assessed. STATISTICAL TESTS: Optimal cut-off value was determined using receiver operating characteristic curve and Youden method. Survival analysis was performed using Kaplan-Meier and Cox proportional hazard. Discriminative power of models was compared using net reclassification improvement and integrated discriminatory index. P value <0.05 was considered statistically significant. RESULTS: 47.2% patients reached primary endpoints; 25.8% patients reached secondary endpoints. Patients with elevated liver ECV (cut-off 34.4%) had significantly higher risk reaching primary and secondary endpoints. Cox regression showed liver ECV was an independent prognostic predictor, and showed independent prognostic value for primary endpoints and long-term HF readmission compared to conventional clinical and cardiac MRI parameters. DATA CONCLUSIONS: Liver ECV is an independent prognostic predictor and may serve as an innovative approach for risk stratification for DCM. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Assessing Challenges of 2D-Molybdenum Ditelluride for Efficient Hydrogen Generation in a Full-Scale Proton Exchange Membrane (PEM) Water Electrolyzer.

Proton exchange membrane (PEM) water electrolyzers are critical enablers for sustainable green hydrogen production due to their high efficiency. However, nonplatinum catalysts are rarely evaluated under actual electrolyzer operating conditions, limiting knowledge of their feasibility for H2 production at scale. In this work, metallic 1T'-MoTe2 films were synthesized on carbon cloth supports via chemical vapor deposition and tested as cathodes in PEM electrolysis. Initial three-electrode tests revealed that at 100 mA cm-2, the overpotential of 1T'-MoTe2 approached that of leading 1T'-MoS2 systems, confirming its promise as a hydrogen evolution catalyst. However, when tested in a full-scale PEM electrolyzer, 1T'-MoTe2 delivered only 150 mA cm-2 at 2 V, far below expectations. Postelectrolysis analysis revealed an unexpected passivating tellurium layer, likely inhibiting catalytic sites. While initially promising, the unanticipated passivation caused 1T'-MoTe2 to underperform in practice. This highlights the critical need to evaluate emerging electrolyzer catalysts in PEM electrolyzers, revealing limitations of the idealized three-electrode configuration. Moving forward, validation of model systems in actual electrolyzers will be key to identifying robust nonplatinum catalysts for sustainable green hydrogen production.

Management of Isolated Abdominal Aortic Dissection: Indications and Strategies for Treatment.

BACKGROUND: The aim of this paper was to report our experience in the management of isolated abdominal aortic dissection with endovascular aortic repair and conservative treatment. METHODS: A cohort of 22 consecutive patients with isolated abdominal aortic dissection was treated between January 2016 and December 2021. We reviewed the demographics, clinical features, therapeutic modalities and follow-up results. Retrospective data analysis from patient charts was performed. RESULTS: Twenty-two patients were enrolled in this study from 2 centers. The mean age was 66.2 ± 13.3 years. Hypertension was the primary risk factor. Seventeen (72.7%) patients were asymptomatic, and 18 patients were subrenal artery type (type II). A total of 12 patients had successful endovascular repair (EVAR), and 10 patients underwent conservative treatment. In the group receiving conservative treatment, no patients required EVAR during follow-up, and 4 patients died. However, none of them had aortic causes: 2 patients had cardiac causes, the other 2 had cancer, and the others remained symptom-free. The latest computed tomographic angiography images showed that abdominal aortic dissection still existed, and the extent of the false lumen did not increase significantly. CONCLUSIONS: Both conservative treatment and EVAR are effective treatment options. Appropriate treatment needs to be performed according to different patients' clinical manifestations and doctors' experience.

Reference Ranges of Ventricular Morphology and Function in Healthy Chinese Adults: A Multicenter 3 T MRI Study.

BACKGROUND: Magnetic resonance imaging (MRI) reference ranges for ventricular morphology and function in the Chinese population are lacking. PURPOSE: To establish the MRI reference ranges of left and right ventricular (LV and RV) morphology and function based on a large multicenter cohort. STUDY TYPE: Prospective. POPULATION: One thousand and twelve healthy Chinese Han adults. FIELD STRENGTH/SEQUENCE: Balanced steady-state free procession cine sequence at 3.0 T. ASSESSMENT: Biventricular end-diastolic, end-systolic, stroke volume, and ejection fraction (EDV, ESV, SV, and EF), LV mass (LVM), end-diastolic and end-systolic dimension (LVEDD and LVESD), anteroseptal wall thickness (AS), and posterolateral wall thickness (PL) were measured. Body surface area (BSA) and height were used to index biventricular parameters. Parameters were compared between age groups and sex. STATISTICAL TESTS: Independent-samples t-tests or Mann-Whitney U test to compare mean values between sexes; ANOVA or Kruskal-Wallis test to compare mean values among age groups; linear regression to assess the relationships between cardiac parameters and age (correlation coefficient, r). A P value <0.05 was considered statistically significant. RESULTS: The biventricular volumes, LVM, LVEDD, RVEDV/LVEDV ratio, LVESD, AS, and PL were significantly greater in males than in females, even after indexing to BSA or height, while LVEF and RVEF were significantly lower in males than in females. For both sexes, age was significantly negatively correlated with biventricular volumes (male and female: LVEDV [r = -0.491; r = -0.373], LVESV [r = -0.194; r = -0.184], RVEDV [r = -0.639; r = -0.506], RVESV [r = -0.270; r = -0.223]), with similar correlations after BSA normalization. LVEF (r = 0.043) and RVEF (r = 0.033) showed a significant correlation with age in females, but not in males (P = 0.889; P = 0.282). DATA CONCLUSION: MRI reference ranges for biventricular morphology and function in Chinese adults are presented and show significant associations with age and sex. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.

Treatment strategies for hepatic artery complications after pediatric liver transplantation: A systematic review.

This study aimed to evaluate the effectiveness of different treatments for hepatic artery thrombosis (HAT) and hepatic artery stenosis (HAS) after pediatric liver transplantation. We systematically reviewed studies published since 2000 that investigated the management of HAT and/or HAS after pediatric liver transplantation. Studies with a minimum of 5 patients in one of the treatment methods were included. The primary outcomes were technical success rate and graft and patient survival. The secondary outcomes were hepatic artery patency, complications, and incidence of HAT and HAS. Of 3570 studies, we included 19 studies with 328 patients. The incidence was 6.2% for HAT and 4.1% for HAS. Patients with an early HAT treated with surgical revascularization had a median graft survival of 45.7% (interquartile range, 30.7%-60%) and a patient survival of 61.3% (interquartile range, 58.7%-66.9%) compared with the other treatments (conservative, endovascular revascularization, or retransplantation). As for HAS, endovascular and surgical revascularization groups had a patient survival of 85.7% and 100% (interquartile range, 85%-100%), respectively. Despite various treatment methods, HAT after pediatric liver transplantation remains a significant issue that has profound effects on the patient and graft survival. Current evidence is insufficient to determine the most effective treatment for preventing graft failure.

Oxygen vacancy-rich Ag/CuO nanoarray mesh fabricated by laser ablation for efficient bacterial inactivation.

The contamination of drinking water by microbes is a critical health concern, underscoring the need for safe, reliable, and efficient methods to treat pathogenic microorganisms. While most sterilization materials are available in powder form, this presents safety risks and challenges in recycling. Herein, this study reports the preparation of an innovative copper oxide supported silver monolithic nanoarray mesh with abundant oxygen vacancies (Ag/CuO-VO) by laser ablation. The instantaneous high temperature caused by laser ablation preserves the material's original structure while generating oxygen vacancies on the CuO surface. The Ag/CuO-VO mesh demonstrated a remarkable ability to inactivate over 99% of Escherichia coli (E. Coli) within 20 min. The oxygen vacancies in the Ag/CuO-VO enhance interactions between oxygen species and the Ag/CuO-VO, leading to the accumulation of large amounts of reactive oxygen species (ROS). The generated ROS effectively disrupt both layers of the bacterial cell wall - the peptidoglycan and the phospholipid - as confirmed by Fourier Transform Infrared (FTIR) spectroscopy, culminating in cell death. This research presents a monolithic material capable of inactivating pathogenic microorganisms efficiently, offering a significant advancement in water sterilization technology.

Left ventricular underfilling in PAH: A potential indicator for adaptive-to-maladaptive transition.

Pulmonary arterial hypertension (PAH) still remains a life-threatening disorder with poor prognosis. The right ventricle (RV) adapts to the increased afterload by a series of prognostically significant morphological and functional changes, the adaptive nature should also be understood in the context of ventricular interdependence. We hypothesized that left ventricle (LV) underfilling could serve as an important imaging marker for identifying maladaptive changes and predicting clinical outcomes in PAH patients. We prospectively enrolled patients with PAH who underwent both cardiac magnetic resonance and right heart catheterization between October 2013 and December 2020. Patients were categorized into four groups based on their LV and RV mass/volume ratio (M/V). LV M/V was stratified using the normal value (0.7 g/mL for males and 0.6 g/mL for females) to identify patients with LV underfilling (M/V ≥ normal value), while RV M/V was stratified based on the median value. The primary endpoint was all-cause mortality, and the composite endpoints included all-cause mortality and heart failure-related readmissions. A total of 190 PAH patients (53 male, mean age 37 years) were included in this study. Patients with LV underfilling exhibited higher NT-proBNP levels, increased RV mass, larger RV but smaller LV, lower right ventricular ejection fraction, and shorter 6-min walking distance. Patients with LV underfilling had a 2.7-fold higher risk of mortality than those without and LV M/V (hazard ratio [per 0.1 g/mL increase]: 1.271, 95% confidence interval: 1.082-1.494, p = 0.004) was also independent predictors of all-cause mortality. Moreover, patients with low LV M/V had a better prognosis regardless of the level of RV M/V. Thus, LV underfilling is an independent predictor of adverse clinical outcomes in patients with PAH, and it could be an important imaging marker for identifying maladaptive changes in these patients.

Development of enzyme-inorganic hybrid nanoflower-modified electrodes and a smartphone-controlled electrochemical analyzer for point-of-care testing of salivary amylase in saliva.

Quantitation of salivary alpha-amylase (sAA) plays a significant role in not only theoretical studies but also clinical practice. This study reports a quantitative point-of-care testing (POCT) system for sAA quantitation anywhere, anytime and by anyone, which consists of customized electrodes and a smartphone-controlled electrochemical analyzer. Organic-inorganic hybrid nanoflowers (NFs) encapsulating α-glucosidase (AG) and glucose dehydrogenase (GDH) have been synthesized and modified onto screen-printed electrodes (SPCEs) to fabricate the customized electrodes. The SPCEs integrated with the smartphone-controlled electrochemical analyzer exhibit good analytical performance for sAA with a low detection limit of 5.02 U mL-1 and a wide dynamic range of 100-2000 U mL-1 using chronoamperometry. The reported POCT system has been successfully demonstrated for quantitation of sAA in clinical saliva samples, and the quantitation results correlated well with those of the Bernfeld method which is extensively used in clinics. More importantly, this study reveals the great potential of sAA as an early warning indicator of abnormal glucose metabolism in obese individuals. Considering the non-invasive saliva sampling process as well as the easy-to-use and cost-effectiveness features of this quantitative POCT system, quantitation of salivary sAA at home by laypersons might become an appealing choice for obese individuals to monitor their glucose metabolism status anytime.

A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis.

BACKGROUND: Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Emerge evidence suggests that circular RNA (circRNA) is a pivotal player in cancer progression. However, its role in CRC liver metastasis remains largely unknown. METHODS: Circ-YAP expression was detected by qRT-PCR and in situ hybridization. The function of circ-YAP was tested by wound healing, transwell and CCK-8 assays. RNA immunoprecipitation, pull-down, luciferase reporter, chromatin immunoprecipitation assays were used to investigate the mechanism underlying circ-YAP promoting CRC liver metastasis. CRC liver metastasis animal model was established to assess the effect of circ-YAP in vivo. RESULTS: Circ-YAP was notably upregulated in CRC with liver metastasis, which was associated with dismal prognosis. Circ-YAP promoted CRC cell migration and invasion in vitro, and facilitated liver metastasis in patient-derived xenografts (PDX) models in vivo. Mechanistically, circ-YAP encoded a novel truncated protein containing 220 amino acids, termed as YAP-220aa, which competitively bound to LATS1, resulting in YAP dephosphorylation and nuclear translocation, thereby activating a cohort of metastasis-promoting genes. Importantly, N6-methyladenosine (m6A) modification orchestrated efficient initiation of circ-YAP translation, requiring m6A reader YTHDF3 and eIF4G2 translation initiation complex. Intriguingly, circ-YAP was transcriptionally enhanced by YAP/TEAD complex, thus forming a positive regulatory feed-forward loop. CONCLUSIONS: Our findings reveal a previously uncharacterized oncoprotein encoded by circ-YAP, implying a promising biomarker and therapeutic target for CRC patients with liver metastasis.

Vitamin E stabilizes iron and mitochondrial metabolism in pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood. Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study. Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro. Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects.

Reference ranges of myocardial T1 and T2 mapping in healthy Chinese adults: a multicenter 3T cardiovascular magnetic resonance study.

BACKGROUND: Although reference ranges of T1 and T2 mapping are well established for cardiovascular magnetic resonance (CMR) at 1.5T, data for 3T are still lacking. The objective of this study is to establish reference ranges of myocardial T1 and T2 based on a large multicenter cohort of healthy Chinese adults at 3T CMR. METHODS: A total of 1015 healthy Chinese adults (515 men, age range: 19-87 years) from 11 medical centers who underwent CMR using 3T Siemens scanners were prospectively enrolled. T1 mapping was performed with a motion-corrected modified Look-Locker inversion recovery sequence using a 5(3)3 scheme. T2 mapping images were acquired using T2-prepared fast low-angle shot sequence. T1 and T2 relaxation times were quantified for each slice and each myocardial segment. The T1 mapping and extracellular volume standardization (T1MES) phantom was used for quality assurance at each center prior to subject scanning. RESULTS: The phantom analysis showed strong consistency of spin echo, T1 mapping, and T2 mapping among centers. In the entire cohort, global T1 and T2 reference values were 1193 ± 34 ms and 36 ± 2.5 ms. Global T1 and T2 values were higher in females than in males (T1: 1211 ± 29 ms vs. 1176 ± 30 ms, p < 0.001; T2: 37 ± 2.3 ms vs. 35 ± 2.5 ms, p < 0.001). There were statistical differences in global T2 across age groups (p < 0.001), but not in global T1. Linear regression showed no correlation between age and global T1 or T2 values. In males, positive correlation was found between heart rate and global T1 (r = 0.479, p < 0.001). CONCLUSIONS: Using phantom-validated imaging sequences, we provide reference ranges for myocardial T1 and T2 values on 3T scanners in healthy Chinese adults, which can be applied across participating sites. Trial registration URL: http://www.chictr.org.cn/index.aspx . Unique identifier: ChiCTR1900025518. Registration name: 3T magnetic resonance myocardial quantitative imaging standardization and reference value study: a multi-center clinical study.

Pulmonary Transit Time Derived from First-Pass Perfusion Cardiac MR Imaging: A Potential New Marker for Cardiac Involvement and Prognosis in Light-Chain Amyloidosis.

BACKGROUND: First-pass perfusion cardiac MR imaging could reflect pulmonary hemodynamics. However, the clinical value of pulmonary transit time (PTT) derived from first-pass perfusion MRI in light-chain (AL) amyloidosis requires further evaluation. PURPOSE: To assess the clinical and prognostic value of PTT in patients with AL amyloidosis. STUDY TYPE: Prospective observational study. POPULATION: 226 biopsy-proven systemic AL amyloidosis patients (age 58.62 ± 10.10 years, 135 males) and 43 healthy controls (age 42 ± 16.2 years, 20 males). FIELD STRENGTH/SEQUENCE: SSFP cine and phase sensitive inversion recovery late gadolinium enhancement (LGE) sequences, and multislice first-pass myocardial perfusion imaging with a saturation recovery turbo fast low-angle shot (SR-TurboFLASH) pulse sequence at 3.0T. ASSESSMENT: PTT was measured as the time interval between the peaks of right and left ventricular cavity arterial input function curves on first-pass perfusion MR images. STATISTICAL TESTS: Independent-sample t test, Mann-Whitney U test, Chi-square test, Fisher's exact test, analysis of variance, or Kruskal-Wallis test, as appropriate; univariable and multivariable Cox proportional hazards models and Kaplan-Meier curves, area under receiver operating characteristic curve were used to determine statistical significance. RESULTS: PTT could differentiate AL amyloidosis patients with (N = 188) and without (N = 38) cardiac involvement (area under the curve [AUC] = 0.839). During a median follow-up of 35 months, 160 patients (70.8%) demonstrated all-cause mortality. After adjustments for clinical (Hazard ratio [HR] 1.061, confidence interval [CI]: 1.021-1.102), biochemical (HR 1.055, CI: 1.014-1.097), cardiac MRI-derived (HR 1.077, CI: 1.034-1.123), and therapeutic (HR 1.063, CI: 1.024-1.103) factors, PTT predicted mortality independently in patients with AL amyloidosis. Finally, PTT could identify worse outcomes in patients demonstrating New York Heart Association class III, Mayo 2004 stage III, and transmural LGE pattern. DATA CONCLUSION: PTT may serve as a new imaging predictor of cardiac involvement and prognosis in AL amyloidosis. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.