Advancing microbial production through artificial intelligence-aided biology.

Microbial cell factories (MCFs) have been leveraged to construct sustainable platforms for value-added compound production. To optimize metabolism and reach optimal productivity, synthetic biology has developed various genetic devices to engineer microbial systems by gene editing, high-throughput protein engineering, and dynamic regulation. However, current synthetic biology methodologies still rely heavily on manual design, laborious testing, and exhaustive analysis. The emerging interdisciplinary field of artificial intelligence (AI) and biology has become pivotal in addressing the remaining challenges. AI-aided microbial production harnesses the power of processing, learning, and predicting vast amounts of biological data within seconds, providing outputs with high probability. With well-trained AI models, the conventional Design-Build-Test (DBT) cycle has been transformed into a multidimensional Design-Build-Test-Learn-Predict (DBTLP) workflow, leading to significantly improved operational efficiency and reduced labor consumption. Here, we comprehensively review the main components and recent advances in AI-aided microbial production, focusing on genome annotation, AI-aided protein engineering, artificial functional protein design, and AI-enabled pathway prediction. Finally, we discuss the challenges of integrating novel AI techniques into biology and propose the potential of large language models (LLMs) in advancing microbial production.

Establishment of a scoring model for predicting clinical outcomes in patients with unilateral primary aldosteronism after superselective adrenal artery embolization.

OBJECTIVE: Superselective adrenal arterial embolization (SAAE) is a potential alternative treatment for patients with unilateral primary aldosteronism (PA) who refuse unilateral adrenalectomy. Therefore, we aimed to establish a scoring model to differentiate between hypertensive remission after SAAE. METHODS: This prospective cohort study involved 240 patients who underwent SAAE for unilateral PA. Patients were randomly divided into a model training set and a validation set at a ratio of 7:3. The clinical outcome was a response to hypertension remission, defined as complete, partial, or absent success at 6 months after SAAE. Multivariate logistic regression was performed to identify independent parameters and develop a nomogram to predict clinical outcomes after SAAE. The discrimination, calibration efficacy, and clinical utility of the predictive model were assessed. RESULTS: Five independent predictors were identified: female sex, duration of hypertension, defined daily dose of antihypertensive medication, diabetes, and target organ damage. The above five independent predictors were put into a predictive model that was presented as a nomogram. Using bootstrapping for internal validation, the C-statistic for the predictive model was 0.866 (95% confidence interval [CI]: 0.834 to 0.898). In the validation cohort, the area under the curve (AUC) of the nomogram for predicting hypertension remission after SAAE was 0.809. CONCLUSION: The present model is the first nomogram-based score that specifically predicts hypertension remission after SAAE in patients with unilateral PA using conventional parameters. This is an effective risk stratification tool that can be used by clinicians for timely and tailored preoperative risk discussions.

Aerodynamic Simulation of Small Airway Resistance: A New Imaging Biomarker for Chronic Obstructive Pulmonary Disease.

Purpose: To develop a novel method for calculating small airway resistance using computational fluid dynamics (CFD) based on CT data and evaluate its value to identify COPD. Patients and Methods: 24 subjects who underwent chest CT scans and pulmonary function tests between August 2020 and December 2020 were enrolled retrospectively. Subjects were divided into three groups: normal (10), high-risk (6), and COPD (8). The airway from the trachea down to the sixth generation of bronchioles was reconstructed by a 3D slicer. The small airway resistance (RSA) and RSA as a percentage of total airway resistance (RSA%) were calculated by CFD combined with airway resistance and FEV1 measured by pulmonary function test. A correlation analysis was conducted between RSA and pulmonary function parameters, including FEV1/FVC, FEV1% predicted, MEF50% predicted, MEF75% predicted and MMEF75/25% predicted. Results: The RSA and RSA% were significantly different among the three groups (p<0.05) and related to FEV1/FVC (r = -0.70, p < 0.001; r = -0.67, p < 0.001), FEV1% predicted (r = -0.60, p = 0.002; r = -0.57, p = 0.004), MEF50% predicted (r = -0.64, p = 0.001; r = -0.64, p = 0.001), MEF75% predicted (r = -0.71, p < 0.001; r = -0.60, p = 0.002) and MMEF 75/25% predicted (r = -0.64, p = 0.001; r = -0.64, p = 0.001). Conclusion: Airway CFD is a valuable method for estimating the small airway resistance, where the derived RSA will aid in the early diagnosis of COPD.

Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis.

BACKGROUND AND AIM: The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. METHODS AND RESULTS: PubMed, Embase, and the Cochrane Library were searched for cohort and case-control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). CONCLUSIONS: PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.

Dynamic Clustering and Scaling Behavior of Active Particles under Confinement.

A systematic investigation of the dynamic clustering behavior of active particles under confinement, including the effects of both particle density and active driving force, is presented based on a hybrid coarse-grained molecular dynamics simulation. First, a series of scaling laws are derived with power relationships for the dynamic clustering time as a function of both particle density and active driving force. Notably, the average number of clusters N¯ assembled from active particles in the simulation system exhibits a scaling relationship with clustering time t described by N¯âˆt-m. Simultaneously, the scaling behavior of the average cluster size S¯ is characterized by S¯âˆtm. Our findings reveal the presence of up to four distinct dynamic regions concerning clustering over time, with transitions contingent upon the particle density within the system. Furthermore, as the active driving force increases, the aggregation behavior also accelerates, while an increase in density of active particles induces alterations in the dynamic procession of the system.

Intraprocedural Cortisol Measurement Increases Adrenal Vein Cannulation Success Rate in Primary Aldosteronism: A Systematic Review and Meta-analysis.

BACKGROUND: This study aimed to explore the effectiveness of intraprocedural cortisol measurement (IPCM) for the technical success rates of bilateral adrenal vein, right adrenal vein (RAV), and left adrenal vein (LAV) cannulation during adrenal vein sampling (AVS). METHODS: Systematic searches of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were performed from database inception to May 10, 2023, without any restrictions. We estimated the overall effect estimates of outcomes using the Mantel-Haenszel random-effects model. We conducted subgroup analyses, meta-regression, and sensitivity analysis to explore the possible sources of between-study heterogeneity. RESULTS: In total, 3,485 patients from 11 studies (three prospective and eight retrospective) were enrolled. Bilateral selectivity in patients who underwent IPCM during AVS was significantly higher than that in patients who underwent a routine AVS procedure (84% vs. 64%, RR 1.42, 95% confidence interval [CI]: 1.27-1.59, P < 0.01), with significant heterogeneity (I2 = 68%). A 42% relative risk reduction in the failure rate of bilateral adrenal vein cannulation was found in the IPCM group. Moreover, pooled analysis showed a significant increase in the success rates of RAV cannulation (84% vs. 72%, RR 1.21, 95% CI 1.12-1.31, P < 0.01, I2 = 33%) and LAV cannulation (89% vs. 84%, RR 1.05, 95% CI 1.02-1.08, P < 0.01, I2 = 4%) when IPCM was implemented during the AVS procedure compared to the routine AVS procedure. CONCLUSIONS: An IPCM-based strategy during AVS appears to have a significant beneficial effect on improving the success rate of bilateral cannulation, RAV cannulation and LAV cannulation.

Accuracy meets simplicity: A constitutive model for heterogenous brain tissue.

We present a general, hyperelastic, stretch-based potential that shows promise for modeling the mechanics of brain tissue. A specific four-parameter model derived from this general potential outperforms alternative models, such as the modified Ogden model, the Gent model, Demiray model, and machine-learning models, in capturing brain tissue elasticity. Specifically, the stretch-based model achieved R2 values of 0.997, 0.992, and 0.993 (tension, compression, and shear) for the cortex, 0.995, 0.983, and 0.983 for the basal ganglia, 0.994, 0.929, and 0.970 for the corona radiata, and 0.990, 0.896, and 0.969 for the corpus callosum. This work has the potential to advance our understanding of brain tissue mechanics and provides a valuable tool to improve finite element models for the investigation of brain development, injuries, and disease.

A controlled trial of percutaneous adrenal arterial embolization for hypertension in patients with idiopathic hyperaldosteronism.

Our prior study has suggested that percutaneous superselective adrenal arterial embolization (SAAE) with ethanol reduces blood pressure in patients with primary aldosteronism. This study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with idiopathic hyperaldosteronism. In this prospective, randomized, controlled trial, we randomly assigned patients with idiopathic hyperaldosteronism in a 1:1 ratio to undergo SAAE (n = 29) or receive MRA (n = 30) treatment. The primary endpoint was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The secondary endpoints included changes in office blood pressure, home blood pressure, correction of aldosterone-to-renin ratio, and adverse events at 6 months. The mean change in 24-h ambulatory systolic blood pressure from baseline to 6-month follow-up was significantly different between the two groups (-8.4 mmHg; 95% confidence interval, -15.2 to -2.1 mmHg; P < 0.01). Office, home, and ambulatory blood pressure reduction at 6 months was more pronounced in the SAAE group than the MRA group (all P < 0.05). Aldosterone-to-renin ratio was lower in the SAAE group than the MRA group at 1 and 3 months (both P < 0.01), while it had no difference between the two groups at 6 months. None of the patients experienced serious adverse events in the perioperative and 6-month follow-up periods. SAAE, as a hormonal debulking procedure, is superior to MRA in blood pressure control and correction of biochemical abnormalities in patients with idiopathic hyperaldosteronism.

Association of hypertension with the triglyceride-glucose index and its associated indices in the Chinese population: A 6-year prospective cohort study.

The authors aim to assess the correlation between hypertension and the triglyceride-glucose (TyG) index and its associated indices, and to compare their abilities to identify hypertension. Four thousand eight hundred and sixty-six non-hypertensive participants were enrolled from the China National Health Survey in 2009. The data on new-onset hypertension were gathered in both 2011 and 2015. The TyG index and its associated indices were derived from the fasting triglyceride, blood glucose levels, and anthropometric parameters. Multivariate logistic regression analyses and receiver operating characteristic curve analysis were used. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the new-onset hypertension for the TyG-waist-to-height ratio (TyG-WHtR), TyG-waist circumference (TyG-WC), TyG-waist-to-hip ratio (TyG-WHR), TyG-body mass index (TyG-BMI), and TyG index were 1.379 (1.230-1.546), 1.002 (1.001-1.003), 1.156 (1.069-1.251), 1.007 (1.005-1.009), and 1.187 (1.051-1.341), respectively. In addition, comparing the lowest quartile (Q1) group with the highest quartile (Q4), the adjusted OR and 95% CI for the new-onset hypertension were found to be 1.86 (1.48-2.35), 1.93 (1.53-2.43), 1.71 (1.36-2.16), 2.00 (1.60-2.50), and 1.49 (1.19-1.88) for TyG-WHtR, TyG-WC, TyG-WHR, TyG-BMI, and TyG index, respectively, among all participants. The TyG-WHtR had the largest area under the curve (AUC) for hypertension (AUC, 0.628; 95% CI, 0.614-0.641) in all participants. Stratified analysis also indicated that the TyG-WHtR exhibited the greatest AUC in both males (AUC, 0.608; 95% CI, 0.587-0.629) and females (AUC, 0.648; 95% CI, 0.629-0.666). In conclusions, the TyG index and its associated indices were positively associated with hypertension. Among these indices, TyG-WHtR was the most valuable indicator for predicting hypertension.

A modified single-catheter approach for improving adrenal venous sampling in patients with primary aldosteronism.

OBJECTIVES: Adrenal vein sampling (AVS) is an established procedure for assessing subtype patients with primary aldosteronism (PA). However, it is technically challenging, with high failure rates, which limits its application in clinical practice. Our study aimed to evaluate the safety and efficacy of a single-catheter modified approach for AVS. METHODS: The clinical, angiographic, and procedural data of 182 consecutive patients who underwent AVS procedures between May 2020 and May 2023 were collected and analyzed. The single-catheter modified approach was performed as a single 5 F Tiger catheter with only one-time manual reshaping, which was recommended for sequential bilateral adrenal cannulations. RESULTS: Of the 182 consecutive patients, 174 (95.6%) had successful bilateral adrenal cannulation. The single-catheter modified approach was successfully performed to cannulate the right adrenal vein in 176 (96.7%) patients, while another six (3.3%) patients needed at least a second manual reshaping for 5 F Tiger catheters. For left adrenal cannulation, a single-catheter modified approach was successfully used in 179 (98.4%) patients, whereas 5 F Tiger catheters with at least second-time manual reshaping were used in the remaining three (1.6%) patients. The procedural period was 15.6 ± 10.8 min, the fluoroscopy time was 4.2 ± 1.5 min, and the diagnostic contrast was 15.5 ± 4.8 mL. The incidence of procedure-related complications associated with AVS was 1.1%. The cumulative summation assessment illustrated that the learning curve for the operating procedure required up to 29 cases, indicating that the procedure time was shortened after 29 cases. CONCLUSIONS: The single-catheter modified approach is an effective, safe, and feasible technique for AVS treatment. In particular, this improved method is not difficult for beginners with high technical success rates.

Unilateral chemical ablation of the adrenal gland lowers blood pressure and alleviates target organ damage in spontaneously hypertensive rats.

Adrenal gland hormones play a critical role in the development and maintenance of hypertension. Adrenal ablation has been used to treat primary aldosteronism but not essential hypertension. The present study aimed to investigate the effectiveness and safety of unilateral adrenal gland ablation in treating spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of anhydrous ethanol or a sham procedure. Blood pressure was monitored by both tail-cuff plethysmography and telemetry until 6 months after the procedure. Adrenal ablation significantly lowered systolic and diastolic blood pressure of the SHR (P < 0.05 or P < 0.01) but not WKY from 4 to 24 weeks after the procedure. Adrenal ablation substantially damaged adrenal cortex and medulla with fibrosis in SHR and WKY rats. The ablation procedure remarkably reduced the levels of renin, angiotensin II, aldosterone, cortisol, noradrenaline, and epinephrine in SHR (all P < 0.05) but not in WKY. Hypokalemia in SHR was significantly improved by adrenal ablation (P < 0.05), while the serum sodium levels were not affected by adrenal ablation in either SHR or WKY rats. Additionally, adrenal ablation improved cardiac, renal, and vascular remodeling and function measured 3 months after the procedure in SHR. In conclusion, the present study shows that ethanol ablation of adrenal gland can effectively lower blood pressure and prevent target organ damage in SHR. These findings suggest that unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of ethanol or a sham procedure. Blood pressure was monitored for 24 weeks. RESULTS: Adrenal ablation significantly lowered systolic and diastolic blood pressure of SHR but not WKY from 4 to 24 weeks after the procedure. CONCLUSION: Unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

PURPOSE: The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). METHODS: Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. RESULTS: A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (ß, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (ß, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (ß, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (ß, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (ß, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (ß, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. CONCLUSIONS: Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Effect of PCSK9 antibodies on coronary plaque regression and stabilization derived from intravascular imaging in patients with coronary artery disease: A meta-analysis.

BACKGROUND: Despite extensive evidence demonstrating the beneficial effects of the additional PCSK9 antibodies with high-density statins treatment on cardiovascular clinical outcomes, the potent causes underlying these effects remain elusive. This meta-analysis aimed at exploring the underlying causes to assess the effect of PCSK9 antibodies on the regression and stabilization of coronary plaque derived from intravascular imaging in statin-treated patients with coronary artery disease (CAD). METHODS: PubMed, Embase, and Cochrane Library were searched from inception to February 1, 2023, for randomized controlled trials (RCTs), nonrandomized studies without language restrictions if they described the association between PCSK9 antibodies with coronary plaque regression and stabilization evaluated by intravascular imaging in statin-treated patients with CAD. Meta-analyses were performed for mean difference (MD) and odds ratio (OR) using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. RESULTS: A total of 9 studies (7 RCTs and 2 non-RCTs) with 2290 CAD patients were identified and included. Among statin-treated CAD patients, the addition use of PCSK9 antibodies was associated with IVUS-derived percent atheroma volume (PAV) (4 studies with 1875 participants; MD, -1.26; 95% CI, -1.51 to -1.00; P < 0.01), total atheroma volume (TAV) (4 studies with 1875 participants; MD, -7.23; 95% CI, -11.28 to -3.18; P < 0.01), incidence of PAV regression (4 studies with 1875 participants; OR, 2.24; 95% CI, 1.81 to 2.77; P < 0.01) and incidence of TAV regression (3 studies with 1256 participants; OR, 1.66; 95% CI, 1.33 to 2.09; P < 0.01) in Caucasians instead of Asians from multiple countries; OCT-derived minimum fibrous cap thickness (FCT) (6 studies with 841 participants; MD, 25.16; 95% CI, 14.06 to 36.27; P < 0.01), incidence of thin-capped fibroatheroma (TCFA) regression (2 studies with 222 participants; OR, 2.56; 95% CI, 1.42 to 4.61; P < 0.01) and maximum lipid arc (4 studies with 280 participants; MD, -14.96; 95% CI, -22.10 to -7.83; P < 0.01) in Asians and Caucasians without races restrictions. CONCLUSIONS: PCSK9 antibodies resulted in significantly greater coronary plaque regression and stabilization in statin-treated CAD patients, mostly Caucasians from multiple countries. Further studies are needed to assess the effect for Asian patients.

The saturation effect of 25(OH)D level on sleep duration for older people:The NHANES 2011-2018.

This study aimed to investigate the potential relationship between vitamin D and sleep duration in older adults. The study utilized multivariate linear regression models to estimate the associations between serum 25(OH)D and sleep duration. In addition, a smooth curve fitting approach was used to identify any non-linear trends between the two variables. The study included 15,749 participants over the age of 60. The results showed a positive correlation between serum 25(OH)D levels and sleep duration in the fully-adjusted model. This correlation was observed in both males and females, as well as in non-Hispanic White and non-Hispanic Black participants. No significant interactions were found between serum 25(OH)D levels and the stratifying variables. The curve fitting analysis revealed a non-linear relationship between 25(OH)D and sleep duration, with a saturation point observed at a serum 25(OH)D level of 40.6 ng/mL. In conclusion, the findings suggest that there is a positive correlation between serum 25(OH)D levels and sleep duration, with a saturation effect observed. A positive correlation is evident when serum 25(OH)D falls below 40.6 ng/mL.

Transmembrane protein 117 knockdown protects against angiotensin-II-induced cardiac hypertrophy.

Mitochondrial dysfunction plays a critical role in the pathogenesis of pathological cardiac hypertrophy. Transmembrane protein 117 modulate mitochondrial membrane potential that may be involved in the regulation of oxidative stress and mitochondrial function. However, its role in the development of angiotensin II (Ang-II)-induced cardiac hypertrophy is unclear. Cardiac-specific TMEM117-knockout and control mice were subjected to cardiac hypertrophy induced by Ang-II infusion. Small-interfering RNAs against TMEM117 or adenovirus-based plasmids encoding TMEM117 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) before Ang-II stimulation. We found that TMEM117 was upregulated in hypertrophic hearts and cardiomyocytes and TMEM117 deficiency attenuated Ang-II-induced cardiac hypertrophy in vivo. Consistently, the in vitro data demonstrated that Ang-II-induced cardiomyocyte hypertrophy significantly alleviated by TMEM117 knockdown. Conversely, overexpression of TMEM117 exacerbated cardiac hypertrophy and dysfunction. An Ang II-induced increase in cardiac (cardiomyocyte) oxidative stress was alleviated by cardiac-specific knockout (knockdown) of TMEM117 and was worsened by TMEM117 supplementation (overexpression). In addition, TMEM117 knockout decreased endoplasmic reticulum stress induced by Ang-II, which was reversed by TMEM117 supplementation. Furthermore, TMEM117 deficiency mitigated mitochondrial injury in hypertrophic hearts and cardiomyocyte, which was abolished by TMEM117 supplementation (overexpression). Taken together, these findings suggest that upregulation of TMEM117 contributes to the development of cardiac hypertrophy and the downregulation of TMEM117 may be a new therapeutic strategy for the prevention and treatment of cardiac hypertrophy.

An integrated finite element method and machine learning algorithm for brain morphology prediction.

The human brain development experiences a complex evolving cortical folding from a smooth surface to a convoluted ensemble of folds. Computational modeling of brain development has played an essential role in better understanding the process of cortical folding, but still leaves many questions to be answered. A major challenge faced by computational models is how to create massive brain developmental simulations with affordable computational sources to complement neuroimaging data and provide reliable predictions for brain folding. In this study, we leveraged the power of machine learning in data augmentation and prediction to develop a machine-learning-based finite element surrogate model to expedite brain computational simulations, predict brain folding morphology, and explore the underlying folding mechanism. To do so, massive finite element method (FEM) mechanical models were run to simulate brain development using the predefined brain patch growth models with adjustable surface curvature. Then, a GAN-based machine learning model was trained and validated with these produced computational data to predict brain folding morphology given a predefined initial configuration. The results indicate that the machine learning models can predict the complex morphology of folding patterns, including 3-hinge gyral folds. The close agreement between the folding patterns observed in FEM results and those predicted by machine learning models validate the feasibility of the proposed approach, offering a promising avenue to predict the brain development with given fetal brain configurations.

Association between high-mobility group box 2 and subclinical hypertension-mediated organ damage in young adults.

Background: Hypertension-mediated organ damage (HMOD) is an emerging problem among young adults. The potential role of chronic immune-mediated inflammation in the pathogenesis of HMOD is increasingly being recognized. High-mobility group box 2 (HMGB2) is known for its role in the modulation of innate immunity and exerts signaling functions that affect various inflammatory diseases. However, the association between HMGB2 and HMOD in young adults remains unclear. Objectives: The aim of this study was to explore the association between HMGB2 and subclinical HMOD in young adults. Design: This is a cross-sectional study. Methods: Body composition, carotid ultrasound, carotid-femoral PWV (cf-PWV) measures, echocardiography, serum HMGB2 levels, and serum classic cardiometabolic risk factors were measured in 988 untreated young adults. We estimated the risk related to serum HMGB2 using multivariable-adjusted linear and logistic regression models. Then, we conducted a pathway overrepresentation analysis to examine which key biological pathways may be linked to serum HMGB2 in young adults with HMOD. Results: Among the 988 untreated young adults, we identified four distinct hypertension phenotypes: normotension (40.0%), white-coat hypertension (16.0%), masked hypertension (20.9%), and sustained hypertension (23.1%). High levels of serum HMGB2 were related to increased carotid intima-media thickness (cIMT) and left ventricular mass index (LVMI), higher cf-PWV and blood pressure, and a lower estimated glomerular filtration rate (eGFR). Linear regression analysis showed that serum HMGB2 was positively associated with cf-PWV and negatively associated with eGFR in all patients. Multivariate analysis showed that high levels of serum HMGB2 were associated with high odds of subclinical HMOD (damage in at least one organ). Biological pathway analysis indicated that patients with high serum HMGB2 levels had increased activity of pathways, related to endothelial dysfunction, inflammatory processes, and atherosclerosis. Conclusion: High serum concentrations of HMGB2 are associated with an increased risk of subclinical HMOD in untreated young adults.

Adrenal Ablation Versus Mineralocorticoid Receptor Antagonism for the Treatment of Primary Aldosteronism: A Single-Center Prospective Cohort Study.

BACKGROUND: Superselective adrenal arterial embolization (SAAE) is an alternative treatment for patients with primary aldosteronism (PA). This single-center prospective cohort study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with PA who refused unilateral adrenalectomy. METHODS: Of the 140 PA patients who were enrolled in the study and completed 12-month follow-up, 74 patients underwent SAAE and 66 received MRA treatment. The clinical and biochemical outcome was compared at 1, 6, and 12 months after the procedure. RESULTS: Baseline clinical and biochemical characteristics of the patients were similar between groups. Office, home, and ambulatory blood pressure reduction at 1 month after discharge was more pronounced in the SAAE group than MRA group (all P < 0.05) while the blood pressure reduction was comparable between the 2 groups at 6 and 12 months. Patients who underwent SAAE took less antihypertensive medications than the MRA group during 12-month follow-up (P < 0.01). Both SAAE and MRA treatment improved renin suppression, aldosterone-to-renin ratio elevation, and hypokalemia at 6 and 12 months, whereas only SAAE but not MRA reduced plasma aldosterone levels. Moreover, SAAE achieved higher rates of complete clinical and biochemical success than MRA (both P < 0.01). Logistic regression found that complete clinical and biochemical success was only directly associated with diagnosis of unilateral PA in contrast to bilateral PA (P < 0.01). CONCLUSIONS: The present study provides evidence that SAAE is a reasonable choice of treatment in patients with either unilateral or bilateral PA in terms of clinical and biochemical outcomes. This study was registered at Chictr.org.cn (ChiCTR2100045896).

Case report: Percutaneous adrenal arterial embolization cures resistant hypertension.

Background: Primary aldosteronism is a common cause of resistant hypertension. Patients with primary aldosteronism due to aldosterone-producing adenoma are generally treated with unilateral adrenalectomy or medical therapy. Superselective adrenal arterial embolization is an alternative treatment for patients with unilateral primary aldosteronism. Case summary: We present a 39-year-old male patient with a 5-year history of primary aldosteronism and secondary hypertension. The patient refused adrenalectomy while accepted pharmacotherapy. Despite taking adequate dose of spironolactone, the patient experienced repeatedly muscle weakness due to hypokalemia and had poor blood pressure control with left ventricular hypertrophy and renal dysfunction. Aldosterone-producing adenoma in the left adrenal gland was confirmed by computerized tomography and adrenal venous sampling. The left middle adrenal artery, which was confirmed to provide the main arterial supply to the aldosterone-producing adenoma, was embolized by injecting 2 ml ethanol. The embolization normalized his blood pressure for up to 3 months and reversed left ventricular hypertrophy. Conclusion: Superselective adrenal arterial embolization could be an alternative treatment for patients with aldosterone-producing adenoma who refuse adrenalectomy.

Capsaicin Prevents Contrast-Associated Acute Kidney Injury through Activation of Nrf2 in Mice.

Capsaicin, a transient receptor potential vanilloid 1 channel agonist, possesses antioxidative properties through activating nuclear factor-erythroid 2-related factor 2 (Nrf2). As oxidative stress is a major contributor to the development of contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of capsaicin against CA-AKI via Nrf2. C57BL/6J mice were treated with dehydration and iodixanol to establish the model of CA-AKI. For pretreatment, capsaicin (0.3 mg/kg) was given via intraperitoneal injection one hour before iodixanol injection. Nrf2-specific siRNA was given through the tail vein to knock down Nrf2. The CA-AKI mouse model had remarkable mitochondrial fragmentation and dysfunction and apoptosis of tubular cells, overproduction of superoxide in renal tubules, increased renal malondialdehyde, tubular epithelial cell injury, and renal dysfunction. Importantly, pretreatment with capsaicin significantly ameliorated tubular cell injury and renal dysfunction with decreased superoxide, renal malondialdehyde, and apoptotic tubular cells and improved mitochondrial morphology and function in the CA-AKI mouse model. The expression of Nrf2 was increased in the kidney from the CA-AKI mouse model and was further enhanced by capsaicin. Administration of siRNA through the tail vein successfully decreased Nrf2 expression in the kidney, and knockdown of Nrf2 by siRNA abolished the beneficial effects of capsaicin on CA-AKI. The present study demonstrated a protective effect of capsaicin pretreatment against CA-AKI via Nrf2.