MYH7 mutation is associated with mitral valve leaflet elongation in patients with obstructive hypertrophic cardiomyopathy.

Mitral valve (MV) leaflet elongation is recognized as a primary phenotypic expression of hypertrophic cardiomyopathy (HCM) that contributes to obstruction. This study investigates the correlation between MV length and genotype mutations in the two predominant genes, myosin-binding protein C (MYBPC3), and the ß-myosin heavy chain (MYH7) in patients with obstructive HCM (OHCM). Among the 402 OHCM patients, there were likely pathogenic or pathogenic variations in MYH7 (n = 94) and MYBPC3 (n = 76), along with a mutation-negative group (n = 212). Compared to genotype-negative patients, genotype-positive individuals exhibited elongated MV length, thicker interventricular septum, and increased instances of late gadolinium enhancement. Notably, MYH7 mutations were associated with a more severe disease trajectory than MYBPC3 mutations. After adjusting for potential confounders, multivariate linear regression analysis revealed that MYH7 gene mutations and left ventricular volume were independently associated with MV leaflet elongation. The study indicates that mutations in MYH7 and hemodynamics factors are significant risk factors for elongated MV leaflet. Consequently, regular assessment of MV length, especially in patients with MYH7 mutation and enlarged LV volume, is crucial for timely preoperative strategic planning and improved prognosis.

Physical Frailty and the Risk of Degenerative Valvular Heart Disease.

Background and Objectives: The relationship between physical frailty, age-related conditions, and the incidence of degenerative valvular heart disease (VHD) remains unclear. This study aimed to investigate the potential association between physical frailty and the development of degenerative VHD. Research Design and Methods: Participants from the UK Biobank who were initially free of VHD and heart failure were categorized into 3 groups based on the frailty phenotype: non-frailty, pre-frailty, and frailty. The frailty phenotype was determined by evaluating the following 5 components: weight loss, exhaustion, reduced physical activity, slow gait speed, and low grip strength. The incidence of degenerative VHD, including mitral valve regurgitation (MR), aortic valve regurgitation (AR), and aortic valve stenosis (AS), was assessed using hospital admission or death registries. Results: Among the 331 642 participants, 11 885 (3.6%) exhibited frailty and 143 379 (43.2%) were categorized as pre-frailty. During a median follow-up of 13.8 years, there were 3 684 MR, 1 205 AR, and 3 166 AS events. Compared to non-frailty participants, those with pre-frailty and frailty showed significantly increased risks for MR (hazard ratio [HR], HRpre-frailty:1.19, 95% confidence interval [CI]: 1.11-1.28; HRfrailty: 1.50, 95% CI: 1.30-1.74), AR (HRpre-frailty:1.19, 95% CI: 1.05-1.34; HRfrailty: 1.58, 95% CI: 1.22-2.04), and AS (HRpre-frailty:1.19, 95% CI: 1.11-1.29; HRfrailty: 1.74, 95% CI: 1.51-2.00). Among the 5 components, slow gait speed showed the strongest association with the risk of various types of VHD (HRMR: 1.50, 95% CI: 1.34-1.65; HRAR: 1.50, 95% CI: 1.24-1.80; HRAS: 1.46, 95% CI: 1.32-1.62), followed by exhaustion, low grip strength, and weight loss. Discussion and Implications: Pre-frailty and frailty were associated with a higher risk of all 3 types of degenerative VHD. Early detection and intervention for pre-frailty and frailty in middle-aged and older individuals may assist in preventing or delaying the onset of degenerative VHD.

Interfacial modification of recombinant protein for immunoglobulin G adsorption with spindle-shaped MOF as nano molecular containers.

Development of fresh solid phase extractant is critical for selective separation and purification of special proteins. Herein, we demonstrated a recombinant Staphylococcal Protein G (rSPG) with a His-tag modified the novel single-metal organic framework (rSPG@Ni-MOF-74). The proposed solid-phase extraction material possessed a uniform spindle-shaped structure, large surface area (709.60 m2 g-1) and pore volume (0.08 m3 g-1), high metal content (22.57 wt%), which facilitated the interaction between host and guest. As results, the composite displayed outstanding selective recognition and adsorption of IgG, due to synergistic effect of the binding ability of rSPG with the Fc region of IgG, maintained through hydrogen bonding and electrostatic attraction, as well as hydrophobic interaction. The adsorption performance and mechanism of rSPG@Ni-MOF-74 have been fully investigated. Additionally, the rSPG@Ni-MOF-74 composite could effectively separate IgG from serum obtained from healthy humans, with the purity of the separated IgG verified through SDS-PAGE analysis. Furthermore, LC-MS/MS analysis identified a high content of IgG (55.3 %) in the eluate from rSPG@Ni-MOF-74, suggesting the great potential of rSPG@Ni-MOF-74 in IgG separation and enrichment from complex matrix.

Emergency rescue of a patient with hemorrhagic shock caused by superior mesenteric artery rupture: A case report.

BACKGROUND: Superior mesenteric artery (SMA) injuries rarely occur during blunt abdominal injuries, with an incidence of < 1%. The clinical manifestations mainly include abdominal hemorrhage and peritoneal irritation, which progress rapidly and are easily misdiagnosed. Quick and accurate diagnosis and timely effective treatment are greatly significant in managing emergent cases. This report describes emergency rescue by a multidisciplinary team of a patient with hemorrhagic shock caused by SMA rupture. CASE SUMMARY: A 55-year-old man with hemorrhagic shock presented with SMA rupture. On admission, he showed extremely unstable vital signs and was unconscious with a laceration on his head, heart rate of 143 beats/min, shallow and fast breathing (frequency > 35 beats/min), and blood pressure as low as 20/10 mmHg (1 mmHg = 0.133 kPa). Computed tomography revealed abdominal and pelvic hematocele effusion, suggesting active bleeding. The patient was suspected of partial rupture of the distal SMA branch. The patient underwent emergency mesenteric artery ligation, scalp suture, and liver laceration closure. In view of conditions with acute onset, rapid progression, and high bleeding volume, key points of nursing were conducted, including activating emergency protocol, opening of the green channel, and arranging relevant examinations with various medical staff for quick diagnosis. The seamless collaboration of the multidisciplinary team helped shorten the preoperative preparation time. Emergency laparotomy exploration and mesenteric artery ligation were performed to mitigate hemorrhagic shock while establishing efficient venous accesses and closely monitoring the patient's condition to ensure hemodynamic stability. Strict measures were taken to avoid intraoperative hypothermia and infection. CONCLUSION: After 3.5 h of emergency rescue and medical care, bleeding was successfully controlled, and the patient's condition was stabilized. Subsequently, the patient was transferred to the intensive care unit for continuous monitoring and treatment. On the sixth day, the patient was weaned off the ventilator, extubated, and relocated to a specialized ward. Through diligent medical intervention and attentive nursing, the patient made a full recovery and was discharged on day 22. The follow-up visit confirmed the patient's successful recovery.

Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Projection neurons from medial entorhinal cortex to basolateral amygdala are critical for the retrieval of morphine withdrawal memory.

The medial entorhinal cortex (MEC) is crucial for contextual memory, yet its role in context-induced retrieval of morphine withdrawal memory remains unclear. This study investigated the role of the MEC and its projection neurons from MEC layer 5 to the basolateral amygdala (BLA) (MEC-BLA neurons) in context-induced retrieval of morphine withdrawal memory. Results show that context activates the MEC in morphine withdrawal mice, and the inactivation of the MEC inhibits context-induced retrieval of morphine withdrawal memory. At neural circuits, context activates MEC-BLA neurons in morphine withdrawal mice, and the inactivation of MEC-BLA neurons inhibits context-induced retrieval of morphine withdrawal memory. But MEC-BLA neurons are not activated by conditioning of context and morphine withdrawal, and the inhibition of MEC-BLA neurons do not influence the coupling of context and morphine withdrawal memory. These results suggest that MEC-BLA neurons are critical for the retrieval, but not for the formation, of morphine withdrawal memory.

Formation of chronic morphine withdrawal memories requires C1QL3-mediated regulation of PSD95 in the mouse basolateral amygdala.

Chronic morphine withdrawal memory formation is a complex process influenced by various molecular mechanisms. In this study, we aimed to investigate the contributions of the basolateral amygdala (BLA) and complement component 1, q subcomponent-like 3 (C1QL3), a secreted and presynaptically targeted protein, to the formation of chronic morphine (repeat dosing of morphine) withdrawal memory using conditioned place aversion (CPA) and chemogenetic methods. We conducted experiments involving the inhibition of the BLA during naloxone-induced withdrawal to assess its impact on CPA scores, providing insights into the significance of the BLA in the chronic morphine memory formation process. We also examined changes in C1ql3/C1QL3 expression within the BLA following conditioning. Immunofluorescence analysis revealed the colocalization of C1QL3 and the G protein-coupled receptor, brain-specific angiogenesis inhibitor 3 (BAI3) in the BLA, supporting their involvement in synaptic development. Moreover, we downregulated C1QL3 expression in the BLA to investigate its role in chronic morphine withdrawal memory formation. Our findings revealed that BLA inhibition during naloxone-induced withdrawal led to a significant reduction in CPA scores, confirming the critical role of the BLA in this memory process. Additionally, the upregulation of C1ql3 expression within the BLA postconditioning suggested its participation in withdrawal memory formation. The colocalization of C1QL3 and BAI3 in the BLA further supported their involvement in synaptic development. Furthermore, downregulation of C1QL3 in the BLA effectively hindered chronic morphine withdrawal memory formation, emphasizing its pivotal role in this process. Notably, we identified postsynaptic density protein 95 (PSD95) as a potential downstream effector of C1QL3 during chronic morphine withdrawal memory formation. Blocking PSD95 led to a significant reduction in the CPA score, and it appeared that C1QL3 modulated the ubiquitination-mediated degradation of PSD95, resulting in decreased PSD95 protein levels. This study underscores the importance of the BLA, C1QL3 and PSD95 in chronic morphine withdrawal memory formation. It provides valuable insights into the underlying molecular mechanisms, emphasizing their significance in this intricate process.

Progress and Opportunities in Photocatalytic, Electrocatalytic, and Photoelectrocatalytic Production of Hydrogen Peroxide Coupled with Biomass Valorization.

Hydrogen peroxide (H2O2) has been considered an energy carrier (fuel) and oxidizer for various chemical synthesis and environmental remediation processes. Biomass valorization can generate high-value-added products in a green and pollution-free way to solve the energy and environmental crisis. The biomass valorization coupled with H2O2 generation via photo-, electro-, and photoelectrocatalysis plays a positive role in sustainable targets, which can maximize energy utilization and realize the production of value-added products and fuel synthesis. Recently, catalyst design and mechanism studies in H2O2 generation coupled with biomass valorization are in the infancy stage. Herein, this review begins with a background on photo-, electro-, and photoelectrocatalytic techniques for H2O2 generation, biomass valorization, and the H2O2 generation couples with biomass valorization. Meanwhile, the progress and reaction mechanism are reviewed. Finally, the prospects and challenges of a synergistic coupled system of H2O2 synthesis and value-added biomass in achieving high conversion, selectivity, and reaction efficiency are envisioned.

Heavily Doped Carbon Nitride Nanocrystal Promotes Visible-Near-Infrared Photosynthesis of Hydrogen Peroxide with Near-Unit Photon Utilization.

Direct photosynthesis of hydrogen peroxide (H2O2) from water and oxygen represents an intriguing alternative to the current indirect process involving the reduction and oxidation of quinones. However, limited light utilization and sluggish charge transfer largely impede overall photocatalytic efficiency. Herein, we present a heavily doped carbon nitride (CNKLi) nanocrystal for efficient and selective photoproduction of H2O2 via a two-electron oxygen reduction reaction (ORR) pathway. CNKLi induces metal-to-ligand charge transfer (MLCT) and electron trapping, which broadens the light absorption to the visible-near-infrared (vis-NIR) spectrum and prolongs the photoelectron lifetime to the microsecond time scale with an exceptional charge diffusion length of ∼1200 nm. Near-unit photoutilization with an apparent quantum yield (AQY) of 100% for H2O2 generation is achieved below 420 nm. Impressively, CNKLi exhibits an appreciable AQY of 16% at 700 nm, which reaches the absorption capacity (∼16%), thus suggesting a near-unit photon utilization <700 nm. In situ characterization and theoretical calculations reveal the facilitated charge transfer from K+ to the heptazine ring skeleton. These findings provide an approach to improve the photosynthetic efficiency of direct H2O2 preparation in the vis-NIR region and expand applications for driving kinetically slow and technologically desirable oxidations or high-value chemical generation.

In situ growth of binder-free CoNi0.5-MOF/CC electrode for high-performance flexible solid-state supercapacitor application.

Metal organic frameworks (MOFs) with binder-free electrodes have shown promise for portable electrochemical energy storage applications. However, their low specific capacitance and challenges associated with the attachment of active materials to the substrate constrain their practical utility. In this research, we prepared a CoNi0.5-MOF/CC electrode by in situ growth of CoNi0.5-MOF on an H2O2-pretreated carbon cloth (CC) without using any binder. It exhibits a higher specific capacitance of 1337.5 F g-1 than that of CoNi0.5-MOF (∼578 F g-1) at a current density of 1 A g-1 and an excellent rate ability of 88% specific capacitance retention at a current density of 10 A g-1 after 6000 cycles. The as-assembled flexible asymmetric solid-state supercapacitor based on the CoNi0.5-MOF/CC positive electrode and a nitrogen-doped graphene (N-Gr) negative electrode exhibits an energy density of 61.46 W h kg-1 at a power density of 1244.56 W kg-1 and holds a stable capacitance of ∼125 F g-1 at 1 A g-1 when the flexible supercapacitor is bent, showing great potential for flexible electronics application. The H2O2 is indicated to play an important role, enhancing the adhesion of CoNi0.5-MOF on CC and reducing its charge transfer resistance by functionalizing the carbon fiber during the pretreatment of the CC matrix. The results provide a great way to prepare a flexible asymmetric solid-state supercapacitor with both high power density and high energy density for practical application.

MicroRNA let-7c-5p Alleviates in Hepatocellular Carcinoma by Targeting Enhancer of Zeste Homolog 2: A Study Intersecting Bioinformatic Analysis and Validated Experiments.

Enhancer of zeste homolog 2 (EZH2)gene has a prognostic role in hepatocellular carcinoma (HCC). This study aimed to identify the role of microRNAs (miRNAs) let-7c-5p by targeting EZH2 in HCC. We downloaded gene and miRNA RNA-seq data from The Cancer Genome Atlas (TCGA) database. Differences in EZH2 expression between different groups were analyzed and the association of EZH2 expression with HCC prognosis was detected using Cox regression analysis. The miRNA-EZH2-pathway network was constructed. Dual-luciferase reporter assay was performed to detect the hsa-let-7c-5p-EZH2. Cell proliferation, migration, invasion, and apoptosis were detected by CCK-8, Wound healing, Transwell, and Flow cytometry, respectively. RT-qPCR and Western blot were used to detect the expression of let-7c-5p and EZH2. EZH2 was upregulated in HCC tumors (P < 0.0001). Cox regression analysis showed that TCGA HCC patients with high EZH2 expression levels showed a short survival time [hazard ratio (HR) = 1.677, 95% confidence interval (CI) 1.316-2.137; P < 0.0001]. Seven miRNAs were negatively correlated with EZH2 expression and were significantly downregulated in HCC tumor samples (P < 0.0001), in which hsa-let-7c-5p was associated with prognosis in HCC (HR = 0.849 95% CI 0.739-0.975; P = 0.021). We identified 14 immune cells that showed significant differences in EZH2 high- and low-expression groups. Additionally, let-7c-5p inhibited HCC cell proliferation, migration, and invasion and reversed the promoted effects of EZH2 on HCC cell malignant characteristics. hsa-let-7c-5p-EZH2 significantly suppressed HCC malignant characteristics, which can be used for HCC prognosis.

Myocardial bridging in obstructive hypertrophic cardiomyopathy: a risk factor for myocardial fibrosis.

BACKGROUND: Myocardial bridging (MB) is common in patients with hypertrophic cardiomyopathy (HCM). There are sparse data on the impact of MB on myocardial fibrosis in HCM. This study was designed to evaluate the relationship between MB and myocardial fibrosis in patients with obstructive HCM. METHODS: In this cohort study, retrospective data were collected from a high-volume HCM center. Patients with obstructive HCM who underwent septal myectomy and preoperative cardiac magnetic resonance (CMR) were screened from 2011 to 2018. RESULTS: Finally, 492 patients were included in this study, with an average age of 45.7 years. Of these patients, 76 patients had MB. MB occurred mostly in the left anterior descending artery (73/76). The global extent of late gadolinium enhancement (LGE) was correlated with the degree of systolic compression (r = 0.33, p = 0.003). Multivariable linear regression analysis revealed that the degree of systolic compression was an independent risk factor for LGE (ß = 0.292, p = 0.007). The LGE fraction of basal and mid anteroseptal segments in patients with severe MB (compression ratio ≥ 80%) was significantly greater than that in patients with mild to moderate MB (compression ratio < 80%). During a median follow-up of 28 (IQR: 15-52) months, 15 patients died. Kaplan-Meier analysis did not identify differences in all-cause death (log-rank p = 0.63) or cardiovascular death (log-rank p = 0.72) between patients undergoing MB-related surgery and those without MB. CONCLUSIONS: MB with severe systolic compression was significantly associated with a high extent of fibrosis in patients with obstructive HCM. Concomitant myotomy or coronary artery bypass grafting might provide excellent survival similar to that of patients without MB. Identification of patients with severe MB and providing comprehensive management might help improve the prognosis of patients with HCM.

Different projection neurons of basolateral amygdala participate in the retrieval of morphine withdrawal memory with diverse molecular pathways.

Context-induced retrieval of drug withdrawal memory is one of the important reasons for drug relapses. Previous studies have shown that different projection neurons in different brain regions or in the same brain region such as the basolateral amygdala (BLA) participate in context-induced retrieval of drug withdrawal memory. However, whether these different projection neurons participate in the retrieval of drug withdrawal memory with same or different molecular pathways remains a topic for research. The present results showed that (1) BLA neurons projecting to the prelimbic cortex (BLA-PrL) and BLA neurons projecting to the nucleus accumbens (BLA-NAc) participated in context-induced retrieval of morphine withdrawal memory; (2) there was an increase in the expression of Arc and pERK in BLA-NAc neurons, but not in BLA-PrL neurons during context-induced retrieval of morphine withdrawal memory; (3) pERK was the upstream molecule of Arc, whereas D1 receptor was the upstream molecule of pERK in BLA-NAc neurons during context-induced retrieval of morphine withdrawal memory; (4) D1 receptors also strengthened AMPA receptors, but not NMDA receptors, -mediated glutamatergic input to BLA-NAc neurons via pERK during context-induced retrieval of morphine withdrawal memory. These results suggest that different projection neurons of the BLA participate in the retrieval of morphine withdrawal memory with diverse molecular pathways.

Mitral Valve Prolapse in Obstructive Hypertrophic Cardiomyopathy.

Obstructive hypertrophic cardiomyopathy (oHCM) and mitral valve (MV) prolapse (MVP) are the 2 conditions which could cause symptomatic heart failure and sudden cardiac death. The clinical characteristics and surgical outcomes of patients with oHCM and MVP have not been well reported. From April 2012 to February 2018, 84 patients with oHCM (28 patients with MVP and 56 gender- and age-matched patients without MVP) who underwent septal myectomy at our institution were enrolled in this study. Information on clinical characteristics and outcomes was obtained from electronic medical records and follow-up surveys. Compared with those without MVP, patients with MVP were more symptomatic (New York Heart Association class III to IV; 96% vs 77%), more often moderate-to-severe mitral regurgitation (86% vs 48%), atrial fibrillation (39% vs 11%) and higher incidence of nonsustained ventricular tachycardia (44% vs 15%). Twenty (71%) had MV repair and 8 (29%) had MV replacement. Compared with patients without MVP, those with MVP had a longer postoperative hospital stay (10.9 ± 6.4 vs 7.8 ± 2.8 days). None of the 84 study patients died during hospital or follow-up. At the most recent echocardiographic evaluation, left ventricular outflow tract gradient significantly decreased from 69.7 ± 35.4 millimeters of mercury to 7.3 ± 5.1 millimeters of mercury and the degree of mitral valve regurgitation improved from grade 2.43 ± 0.69 to grade 0.5 ± 0.69. In conclusion, MVP occurs rarely in oHCM, and was related to atrial fibrillation, ventricular arrhythmia and mitral regurgitation. Mitral valve surgery in combination with myectomy is effective and safe for patients with oHCM and MVP, relieving substantially left ventricular outflow tract gradients and mitral regurgitation.

Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study.

BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence. METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD. RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD. CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.

Molecular docking-based virtual screening and dynamics simulation study of novel and potential SIRT7 inhibitors.

In cancer cells, short for sirtuin (SIRT7) stabilizes the transformed state via its nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. Epigenetic factor SIRT7 plays important roles in cancer biology, reversing cancer phenotypes and suppressing tumor growth when inactive. In the present study, we got the SIRT7 protein structure from Alpha Fold2 Database and performed structure-based virtual screening to develop specific SIRT7 inhibitors using the SIRT7 inhibitor 97,491 interaction mechanism. As candidates for specific SIRT7 inhibitors, compounds with high affinities to SIRT7 were chosen. ZINC000001910616 and ZINC000014708529, two of our leading compounds, showed strong interactions with SIRT7. Our MD simulation results also revealed that the 5-hydroxy-4H-thioxen-4-one group and terminal carboxyl group were critical groups responsible for interaction of small molecules with SIRT7. In our study, we demonstrated that targeting SIRT7 may offer novel therapeutic options for cancer treatment. Compounds ZINC000001910616 and ZINC000014708529 can serve as chemical probes to investigate SIRT7 biological functions and provide starting points for the development of novel therapeutics against cancers.

Corrected MRI Pulmonary Transit Time for Identification of Combined Precapillary and Postcapillary Pulmonary Hypertension in Patients With Left Heart Disease.

BACKGROUND: The identification of combined precapillary and postcapillary pulmonary hypertension (CpcPH) in patients with pulmonary hypertension (PH) due to left heart disease (LHD) can influence therapy and outcome and is currently based on invasively determined hemodynamic parameters. PURPOSE: To investigate the diagnostic value of MRI-derived corrected pulmonary transit time (PTTc) in PH-LHD sub-grouped according to hemodynamic phenotypes. STUDY TYPE: Prospective observational study. POPULATION: A total of 60 patients with PH-LHD (18 with isolated postcapillary PH [IpcPH] and 42 with CpcPH), and 33 healthy subjects. FIELD STRENGTH/SEQUENCE: A 3.0 T/balanced steady-state free precession cine and gradient echo-train echo planar pulse first-pass perfusion. ASSESSMENT: In patients, right heart catheterization (RHC) and MRI were performed within 30 days. Pulmonary vascular resistance (PVR) was used as the diagnostic "reference standard." The PTTc was calculated as the time interval between the peaks of the biventricular signal-intensity/time curve and corrected for heart rate. PTTc was compared between patient groups and healthy subjects and its relationship to PVR assessed. The diagnostic accuracy of PTTc for distinguishing IpcPH and CpcPH was determined. STATISTICAL TESTS: Student's t-test, Mann-Whitney U-test, linear and logistic regression analysis, and receiver-operating characteristic curves. Significance level: P < 0.05. RESULTS: PTTc was significantly prolonged in CpcPH compared with IpcPH and normal controls (17.28 ± 7.67 vs. 8.82 ± 2.55 vs. 6.86 ± 2.11 seconds), and in IpcPH compared with normal controls (8.82 ± 2.55 vs. 6.86 ± 2.11 seconds). Prolonged PTTc was significantly associated with increased PVR. Furthermore, PTTc was a significantly independent predictor of CpcPH (odds ratio: 1.395, 95% confidence interval: 1.071-1.816). The area under curve was 0.852 at a cut-off value of 11.61 seconds for PTTc to distinguish between CpcPH and IpcPH (sensitivity 71.43% and specificity 94.12%). DATA CONCLUSION: PTTc may be used to identify CpcPH. Our findings have potential to improve selection for invasive RHC for PH-LHD patients. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Association of Life's Essential 8 with all-cause and cardiovascular mortality among US adults: A prospective cohort study from the NHANES 2005-2014.

BACKGROUND AND AIMS: This study aims to investigate the association of Life's Essential 8 (LE8), the recently updated algorithm for quantifying cardiovascular health (CVH) by the American Heart Association (AHA), with long-term outcomes among US adults. METHODS AND RESULTS: This population-based prospective cohort study analyzed data of 23,110 participants aged 20 years or older from the National Health and Nutrition Examination Survey from 2005 to 2014 and their linked mortality data through December 2019. LE8 score (range 0-100) was measured according to AHA definitions and was categorized into low (0-49), moderate (50-79), and high (80-100) CVH. The weighted mean age of the study population was 47.0 years (95% confidence interval [CI], 46.4-47.5 years), and 11,840 were female (weighted percentage, 51.5%; 95% CI, 50.9-52.1%). During a median follow-up period of 113 months (up to 180 months), 2942 all-cause deaths occurred, including 738 CVD deaths. The LE8 score was significantly and inversely related to mortality from all causes (adjusted hazard ratio [HR] for per 10-score increase in LE8 score, 0.86; 95% CI, 0.82-0.90) and cardiovascular disease (adjusted HR for per 10-score increase in LE8 score, 0.81; 95% CI, 0.75-0.87). Compared with participants having low CVH, those having high CVH had a reduction of 40% (adjusted HR, 0.60; 95% CI, 0.48-0.75) in the risk for all-cause mortality and 54% (adjusted HR, 0.46; 95% CI, 0.31-0.68) in the risk for cardiovascular mortality. CONCLUSIONS: Higher LE8 score was independently associated with lower risks of all-cause and cardiovascular mortality among US adults.

Nucleus accumbens circuit disinhibits lateral hypothalamus glutamatergic neurons contributing to morphine withdrawal memory in male mice.

The lateral hypothalamus (LH) is physiologically critical in brain functions. The LH also plays an important role in drug addiction. However, neural circuits underlying LH involvement of drug addiction remain obscure. In the present study,our results showed that in male mice, during context-induced expression of morphine withdrawal memory, LH glutamatergic neurons played an important role; dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) projecting from the core of nucleus accumbens (NAcC) to the LH were an important upstream circuit to activate LH glutamatergic neurons; D1-MSNs projecting from the NAcC to the LH activated LH glutamatergic neurons through inhibiting LH local gamma-aminobutyric acid (GABA) neurons. These results suggest that disinhibited LH glutamatergic neurons by neural circuits from the NAcC importantly contribute to context-induced the expression of morphine withdrawal memory.

Associations between life's essential 8 and non-alcoholic fatty liver disease among US adults.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is closely associated with Cardiovascular disease (CVD). We aim to examine the association of Life's Essential 8 (LE8), the recently updated measurement of cardiovascular health (CVH), with the presence of NAFLD among US adults. METHODS: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey in 2017-2018 and included adults 20 years or older. LE8 score (range 0-100) was measured according to American Heart Association definitions and was categorized into low (0-49), moderate (50-79), and high (80-100) CVH. NAFLD was determined by transient elastography measured hepatic steatosis in the absence of other liver diseases and excess alcohol use. Multivariable logistic and restricted cubic spline models were used to assess the associations. RESULTS: Among 3588 participants included (weighted mean age, 48.0 years; 95% confidence interval [CI] 46.4-49.7 years), 1839 were female (weighted percentage, 51.6%; 95% CI 49.0-54.2%) and 1483 were determined to have NAFLD (weighted percentage, 36.5%; 95% CI 33.3-39.7%). The weighted mean LE8 score of the study population was 67.9 (95% CI 66.6-69.2). After the adjustment of potential confounders, higher LE8 scores were associated with reduced odds of NAFLD (odds ratio [OR] for per 10 score increase, 0.67; 95% CI 0.59-0.76) and a nonlinear dose-response relationship was observed. Similar patterns were also identified in the association of health behavior and health factor scores with NAFLD. The inversed association of LE8 score and NAFLD was significantly stronger among younger, Asian, and participants with higher education and income level. CONCLUSIONS: LE8 and its subscales scores were negatively associated with the presence of NAFLD in non-linear fashions. Promoting adherence to optimal CVH levels may be beneficial to reduce the burden of NAFLD as well as CVD.