Patient-specific analysis of bicuspid aortic valve hemodynamics using a fully coupled fluid-structure interaction model.

Bicuspid aortic valve (BAV), the most common congenital heart disease, is prone to develop significant valvular dysfunction and aortic wall abnormalities such as ascending aortic aneurysm. Growing evidence has suggested that abnormal BAV hemodynamics could contribute to disease progression. In order to investigate BAV hemodynamics, we performed 3D patient-specific fluid-structure interaction (FSI) simulations with fully coupled blood flow dynamics and valve motion throughout the cardiac cycle. Results showed that the hemodynamics during systole can be characterized by a systolic jet and two counter-rotating recirculation vortices. At peak systole, the jet was usually eccentric, with asymmetric recirculation vortices and helical flow motion in the ascending aorta. The flow structure at peak systole was quantified using the vorticity, flow rate reversal ratio and local normalized helicity (LNH) at four locations from the aortic root to the ascending aorta. The systolic jet was evaluated with the peak velocity, normalized flow displacement, and jet angle. It was found that peak velocity and normalized flow displacement (rather than jet angle) gave a strong correlation with the vorticity and LNH in the ascending aorta, which suggests that these two metrics could be used for clinical noninvasive evaluation of abnormal blood flow patterns in BAV patients.

Iridium-Catalyzed Enantioselective Alkene Hydroalkylation via a Heteroaryl-Directed Enolization-Decarboxylation Sequence.

Upon exposure to a cationic Ir(I)-complex modified with the chiral diphosphine DuanPhos, hydroalkylations of styrenes and α-olefins with diverse heteroaryl tert-butyl acetates occur with complete branched selectivity and very high enantioselectivity. The initial adducts undergo acid promoted decarboxylation in situ to provide alkylated heteroarenes possessing defined ß-stereocenters. The processes are postulated to proceed via a stereodefined chiral Ir-enolate, which arises upon heteroarene directed enolization of the heteroaryl acetate precursor. The method can be classified as an enantioselective decarboxylative C(sp3)-C(sp3) cross-coupling.

Proteogenomic characterization of ferroptosis regulators reveals therapeutic potential in glioblastoma.

BACKGROUND: Ferroptosis is iron-dependent non-apoptotic cell death, that is characterized by the excessive accumulation of lipid peroxides. Ferroptosis-inducing therapy also shows promise in the treatment of cancers. However, ferroptosis-inducing therapy for glioblastoma multiforme (GBM) is still in the exploratory stage. METHODS: We identified the differentially expressed ferroptosis regulators using Mann-Whitney U test in the proteome data from Clinical Proteomic Tumor Analysis Consortium (CPTAC). We next analyzed the effect of mutation on protein abundance. A multivariate Cox model was constructed to identify the prognostic signature. RESULTS: In this study, we systemically portrayed the proteogenomic landscape of ferroptosis regulators in GBM. We observed that some mutation-specific ferroptosis regulators, such as down-regulated ACSL4 in EGFR-mutated patients and up-regulated FADS2 in IDH1-mutated patients, were linked to the inhibited ferroptosis activity in GBM. To interrogate the valuable treatment targets, we performed the survival analysis and identified five ferroptosis regulators (ACSL3, HSPB1, ELAVL1, IL33, and GPX4) as the prognostic biomarkers. We also validated their efficiency in external validation cohorts. Notably, we found overexpressed protein and phosphorylation abundances of HSPB1 were poor prognosis markers for overall survival of GBM to inhibit ferroptosis activity. Alternatively, HSPB1 showed a significant association with macrophage infiltration levels. Macrophage-secreted SPP1 could be a potential activator for HSPB1 in glioma cells. Finally, we recognized that ipatasertib, a novel pan-Akt inhibitor, could be a potential drug for suppressing HSPB1 phosphorylation, inducing ferroptosis of glioma cells. CONCLUSION: In summary, our study characterized the proteogenomic landscape of ferroptosis regulators and identified that HSPB1 could be a candidate target for ferroptosis-inducing therapy strategy for GBM.

Genome Instability-Associated Long Non-Coding RNAs Reveal Biomarkers for Glioma Immunotherapy and Prognosis.

Genome instability is a hallmark of tumors and is involved in proliferation, invasion, migration, and treatment resistance of many tumors. However, the relationship of genome instability with gliomas remains unclear. Here, we constructed genome instability-derived long non-coding RNA (lncRNA)-based gene signatures (GILncSig) using genome instability-related lncRNAs derived from somatic mutations. Multiple platforms were used to confirm that the GILncSig were closely related to patient prognosis and clinical characteristics. We found that GILncSig, the glioma microenvironment, and glioma cell DNA methylation-based stemness index (mDNAsi) interacted with each other to form a complex regulatory network. In summary, this study confirmed that GILncSig was an independent prognostic indicator for patients, distinguished high-risk and low-risk groups, and affected immune-cell infiltration and tumor-cell stemness indicators (mDNAsi) in the tumor microenvironment, resulting in tumor heterogeneity and immunotherapy resistance. GILncSig are expected to provide new molecular targets for the clinical treatment of patients with gliomas.

Particle Separation from Liquid Marbles by the Viscous Folding of Liquid Films.

Particle separation from fluid interfaces is one of the major challenges due to the large capillary energy associated with particle adsorption. Previous approaches rely on physicochemical modification or tuning the electrostatic action. Here, we show experimentally that particle separation can be achieved by fast dynamics of drop impact on soap films. When a droplet wrapped with particles (liquid marble) collides with a soap film, it undergoes bouncing and coalescence, stripping and viscous separation, or tunneling through the film. Despite the violence of splashing events, the process robustly yields the stripping in a tunable range. This viscous separation is supported by the transfer front of dynamic contact among the film, particle crust, and drop and can be well controlled in a deterministic manner by selectable impact parameters. By extensive experiments, together with thermodynamic analysis, we disclose that the separation thresholds depend on the energy competition between the kinetic energy, the increased surface energy, and the viscous dissipation. The mechanical cracking of the particle crust arises from the complex coupling between interfacial stress and viscous forces. This study is of potential benefit in soft matter research and also permits the study of a drop with colloid and surface chemistry.

Development and validation of a preoperative MRI-based radiomics nomogram to predict progression-free survival in patients with clival chordomas.

Objectives: The aim of this study was to establish and validate a MRI-based radiomics nomogram to predict progression-free survival (PFS) of clival chordoma. Methods: A total of 174 patients were enrolled in the study (train cohort: 121 cases, test cohort: 53 cases). Radiomic features were extracted from multiparametric MRIs. Intraclass correlation coefficient analysis and a Lasso and Elastic-Net regularized generalized linear model were used for feature selection. Then, a nomogram was established via univariate and multivariate Cox regression analysis in the train cohort. The performance of this nomogram was assessed by area under curve (AUC) and calibration curve. Results: A total of 3318 radiomic features were extracted from each patient, of which 2563 radiomic features were stable features. After feature selection, seven radiomic features were selected. Cox regression analysis revealed that 2 clinical factors (degree of resection, and presence or absence of primary chordoma) and 4 radiomic features were independent prognostic factors. The AUC of the established nomogram was 0.747, 0.807, and 0.904 for PFS prediction at 1, 3, and 5 years in the train cohort, respectively, compared with 0.582, 0.852, and 0.914 in the test cohort. Calibration and risk score stratified survival curves were satisfactory in the train and test cohort. Conclusions: The presented nomogram demonstrated a favorable predictive accuracy of PFS, which provided a novel tool to predict prognosis and risk stratification. Our results suggest that radiomic analysis can effectively help neurosurgeons perform individualized evaluations of patients with clival chordomas.

Preoperative Prediction of Meningioma Consistency via Machine Learning-Based Radiomics.

OBJECTIVES: The aim of this study was to establish and validate a radiomics nomogram for predicting meningiomas consistency, which could facilitate individualized operation schemes-making. METHODS: A total of 172 patients was enrolled in the study (train cohort: 120 cases, test cohort: 52 cases). Tumor consistency was classified as soft or firm according to Zada's consistency grading system. Radiomics features were extracted from multiparametric MRI. Variance selection and LASSO regression were used for feature selection. Then, radiomics models were constructed by five classifiers, and the area under curve (AUC) was used to evaluate the performance of each classifiers. A radiomics nomogram was developed using the best classifier. The performance of this nomogram was assessed by AUC, calibration and discrimination. RESULTS: A total of 3840 radiomics features were extracted from each patient, of which 3719 radiomics features were stable features. 28 features were selected to construct the radiomics nomogram. Logistic regression classifier had the highest prediction efficacy. Radiomics nomogram was constructed using logistic regression in the train cohort. The nomogram showed a good sensitivity and specificity with AUCs of 0.861 and 0.960 in train and test cohorts, respectively. Moreover, the calibration graph of the nomogram showed a favorable calibration in both train and test cohorts. CONCLUSIONS: The presented radiomics nomogram, as a non-invasive prediction tool, could predict meningiomas consistency preoperatively with favorable accuracy, and facilitated the determination of individualized operation schemes.

Fluid-Structure Interaction Analyses of Biological Systems Using Smoothed-Particle Hydrodynamics.

Due to the inherent complexity of biological applications that more often than not include fluids and structures interacting together, the development of computational fluid-structure interaction models is necessary to achieve a quantitative understanding of their structure and function in both health and disease. The functions of biological structures usually include their interactions with the surrounding fluids. Hence, we contend that the use of fluid-structure interaction models in computational studies of biological systems is practical, if not necessary. The ultimate goal is to develop computational models to predict human biological processes. These models are meant to guide us through the multitude of possible diseases affecting our organs and lead to more effective methods for disease diagnosis, risk stratification, and therapy. This review paper summarizes computational models that use smoothed-particle hydrodynamics to simulate the fluid-structure interactions in complex biological systems.

Activation of the Si-B interelement bond related to catalysis.

Si-B reagents, namely silylboronic esters and silylboranes, have become increasingly attractive as versatile reagents to introduce silicon and boron atoms into organic frameworks. Diverse transformations through transition-metal-catalysed or transition-metal-free Si-B bond activation have become available. This Review summarises the recent developments in the now broad field of Si-B chemistry and covers the literature from the last seven years as an update of our review on the same topic published in early 2013 (M. Oestreich, E. Hartmann and M. Mewald, Chem. Rev., 2013, 113, 402-441). It mainly focuses on new applications of Si-B reagents but new methods of their preparation and, where relevant, reaction mechanisms are also discussed.

Enantioselective Synthesis of α-Chiral Propargylic Silanes by Copper-Catalyzed 1,4-Selective Addition of Silicon Nucleophiles to Enyne-Type α,ß,γ,δ-Unsaturated Acceptors.

A copper-catalyzed deconjugative addition of silicon nucleophiles to a broad range of enyne-type α,ß,γ,δ-unsaturated acceptors with high enantiocontrol is reported. The method is 1,4-selective with hardly any formation of the 1,6-adduct. The double-bond geometry is shown to be critical for achieving this chemoselectivity: exclusive 1,4-addition for E and predominant 1,6-addition for Z. By this, E-configured enynoates, enynamides, and enynones have been converted to the corresponding α-chiral propargylic silanes with excellent enantiomeric excesses.

The role of stress concentration in calcified bicuspid aortic valve.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the aging population, and is now believed to be a slow, progressive, yet actively regulated process. The disease progression can be divided into two phases: initiation phase associated with lipid deposition and inflammation response, and the later propagation phase with active calcification growth. It has been hypothesized that elevated mechanical stress plays a major role in both phases of disease progression. In order to identify a direct link between leaflet stress and calcification development, we performed patient-specific finite-element (FE) analyses of six bicuspid aortic valves (BAV), where the leaflets, raphe and calcifications were all considered. The results showed that during the initiation phase, calcium buildup is likely to occur along the leaflet-root attachment curve (ATC), and the commissures, which are subject to the most drastic changes in stress during the cardiac cycle. During the propagation phase, the presence of calcification would lead to local stress concentration along its boundary, hence further calcification growth. Three patterns of calcification formation were identified on BAV leaflets: 'radial', which extended radially from ATC into the leaflet belly region; 'commissure to commissure', which extended circumferentially along the coaptation; and 'raphe', which located in the vicinity of the raphe. Furthermore, we found a strong correlation between regions with a high risk of calcium buildup and regions with elevated mechanical stress. The high-risk regions predicted at diastole on the non-calcified leaflet from FE models agreed reasonably well with the in vivo calcification locations, which indicates that patient-specific FE modelling could help us to evaluate the potential risk of calcification formation in the early stage of CAVD.

A Comprehensive Engineering Analysis of Left Heart Dynamics After MitraClip in a Functional Mitral Regurgitation Patient.

Percutaneous edge-to-edge mitral valve (MV) repair using MitraClip has been recently established as a treatment option for patients with heart failure and functional mitral regurgitation (MR), which significantly expands the number of patients that can be treated with this device. This study aimed to quantify the morphologic, hemodynamic and structural changes, and evaluate the biomechanical interaction between the MitraClip and the left heart (LH) complex of a heart failure patient with functional MR using a fluid-structure interaction (FSI) modeling framework. MitraClip implantation using lateral, central and double clip positions, as well as combined annuloplasty procedures were simulated in a patient-specific LH model that integrates detailed anatomic structures, incorporates age- and gender-matched non-linear elastic material properties, and accounts for mitral chordae tethering. Our results showed that antero-posterior distance, mitral annulus spherecity index, anatomic regurgitant orifice area, and anatomic opening orifice area decreased by up to 28, 39, 52, and 71%, respectively, when compared to the pre-clip model. MitraClip implantation immediately decreased the MR severity and improved the hemodynamic profile, but imposed a non-physiologic configuration and loading on the mitral apparatus, with anterior and posterior leaflet stress significantly increasing up to 210 and 145% during diastole, respectively. For this patient case, while implanting a combined central clip and ring resulted in the highest reduction in the regurgitant volume (46%), this configuration also led to mitral stenosis. Patient-specific computer simulations as used here can be a powerful tool to examine the complex device-host biomechanical interaction, and may be useful to guide device positioning for potential favorable clinical outcomes.

Comparative quantification of primary mitral regurgitation by computer modeling and simulated echocardiography.

Clinical investigations have demonstrated that mitral regurgitation (MR) quantification using echocardiography (echo) may significantly underestimate or overestimate the regurgitant volume, especially for two-dimensional (2D) echo. Computer modeling and simulated echo were conducted to evaluate the fundamental assumptions in the echo quantification of primary MR that is due to posterior mitral leaflet prolapse. The theoretical flaw of the proximal isovelocity surface area (PISA) method originates from the assumption that the MR flow rate is the product of the isovelocity surface area and aliasing velocity, which is only valid when the velocity vectors are perpendicular to the isovelocity surface. Other factors such as the Doppler angle effect, the view planes of 2D echo, and the single time instant of PISA were also analyzed. We find that the hemielliptic PISA method gives the smallest error for moderate and severe MR cases compared with other PISA methods. Compared with the PISA method, the volumetric technique (VT) is theoretically more robust. By considering correction factors that are caused by nonflat velocity profiles and the closing volume of the aortic valve, the accuracy of the VT method can be significantly improved. The corrected volumetric technique provides more accurate results compared with the PISA methods, especially for mild MR.NEW & NOTEWORTHY We evaluate the accuracy of common echocardiography techniques for the quantification of primary mitral regurgitations using computer modeling. The hemielliptic proximal isovelocity surface area (PISA) method gives the smallest error (within 15%) for moderate and severe mitral regurgitation cases compared with other PISA methods. The volumetric method is theoretically more robust than the PISA method. The accuracy of the volumetric method can be improved by a correction factor around 0.7 because of the nonflat velocity profiles and the closing volume of the aortic valve.

The Impact of Self-Expandable Transcatheter Aortic Valve Replacement on Concomitant Functional Mitral Regurgitation: A Comprehensive Engineering Analysis.

BACKGROUND: Mitral regurgitation (MR) is present in a large proportion of patients who undergo transcatheter aortic valve replacement (TAVR). However, existing clinical data on the impact of TAVR on early post-procedural MR severity are contradictory. Using a comprehensive computational engineering methodology, this study aimed to evaluate quantitatively the structural and hemodynamic impact of TAVR on aortic-mitral continuity and MR severity in a rigorously developed and validated patient-specific left heart (LH) computer model with aortic stenosis and concomitant functional MR. METHODS: TAVR procedure was virtually simulated using a self-expandable valve (SEV) at three implantation heights. Pre- and post-TAVR LH dynamics as well as intra-operative biomechanics were analyzed. RESULTS: No significant differences in early MR improvement (<10%) were noted at the three implantation depths when compared to the pre-TAVR state. The high deployment model resulted in the highest stress in the native aortic leaflets, lowest stent-tissue contact force, highest aortic-mitral angle, and highest MR reduction for this patient case. When comparing SEV vs. balloon-expandable valve (BEV) performance at an optimal implantation height, the SEV gave a higher regurgitant volume ⋅ than the pre-TAVR model (40.49 vs 37.59 ml), while the BEV model gave the lowest regurgitant volume (33.84 vs 37.59 ml). CONCLUSIONS: Contact force, aortic-mitral angle, and valve annuli compression were identified as possible mechanistic parameters that may suggest avenues for acute MR improvement. Albeit a single patient parametric study, it is our hope that such detailed engineering analysis could shed some light into the underlying biomechanical mechanisms of TAVR impact on MR.

Transapical mitral valve repair with neochordae implantation: FSI analysis of neochordae number and complexity of leaflet prolapse.

Transapical mitral valve repair with neochordae implantation is a relatively new minimally invasive technique to treat primary mitral regurgitation. Quantifying the complex biomechanical interaction and interdependence between the left heart structures and the neochordae during this procedure is technically challenging. The aim of this parametric computational study is to investigate the immediate effects of neochordae number and complexity of leaflet prolapse on restoring physiologic left heart dynamics after optimal transapical neochordae repair procedures. Neochordae implantation using three and four sutures was modeled under three clinically relevant prolapse conditions: isolated P2, multi-scallop P2/P3, and multi-scallop P2/P1. A fluid-structure interaction (FSI) modeling framework was used to evaluate the left heart dynamics under baseline, prerepair, and postrepair states. Despite immediate restoration of leaflet coaptation and no residual mitral regurgitation in all postrepair models, the average and peak stresses in the repaired scallop(s) increased >40% and >100%, respectively, compared with the baseline state. Additionally, anterior mitral leaflet marginal chordae tension increased >30%, while posterior mitral leaflet chordae tension decreased at least 30%. No marked differences in hemodynamic performance, in native and neochordae forces, and in leaflet stress were found when implanting three or four sutures. We report, to our knowledge, the first set of time-dependent in silico FSI human neochordae tension measurements during transapical neochordae repair. This work represents a further step towards an improved understanding of the biomechanical outcomes of minimally invasive mitral valve repair procedures.

A feasibility study of deep learning for predicting hemodynamics of human thoracic aorta.

Numerical analysis methods including finite element analysis (FEA), computational fluid dynamics (CFD), and fluid-structure interaction (FSI) analysis have been used to study the biomechanics of human tissues and organs, as well as tissue-medical device interactions, and treatment strategies. However, for patient-specific computational analysis, complex procedures are usually required to set-up the models, and long computing time is needed to perform the simulation, preventing fast feedback to clinicians in time-sensitive clinical applications. In this study, by using machine learning techniques, we developed deep neural networks (DNNs) to directly estimate the steady-state distributions of pressure and flow velocity inside the thoracic aorta. After training on hemodynamic data from CFD simulations, the DNNs take as input a shape of the aorta and directly output the hemodynamic distributions in one second. The trained DNNs are capable of predicting the velocity magnitude field with an average error of 1.9608% and the pressure field with an average error of 1.4269%. This study demonstrates the feasibility and great potential of using DNNs as a fast and accurate surrogate model for hemodynamic analysis of large blood vessels.

The impact of balloon-expandable transcatheter aortic valve replacement on concomitant mitral regurgitation: a comprehensive computational analysis.

The aortic and mitral valves function in a reciprocal interdependent fashion. However, the impact of transcatheter aortic valve replacement (TAVR) on the aortic-mitral continuity and severity of mitral regurgitation (MR) are poorly understood. In this study, a comprehensive engineering analysis was performed to investigate the impact of TAVR on MR severity and left heart dynamics in a retrospective patient case who harbours bicuspid aortic valve stenosis and concomitant functional MR. The TAVR procedure was computer simulated using a balloon-expandable valve, and the impact of three implantation heights on aortic-mitral coupling, MR severity and device performance were analysed. The accuracy and predictability of the computer modelling framework were validated with pre- and post-operative echo data. The highest deployment model resulted in higher stresses in the native leaflets, contact radial force and stent recoil, while the midway implantation model gave better haemodynamic performance and MR reduction in this patient case. Although the regurgitant volume decreased (less than 10%) for the three deployment configurations, no significant differences in MR severity improvement and mitral leaflet tethering were found. Acute improvement in MR was (i) due to the mechanical compression of the stent against the aortic-mitral curtain, (ii) due to an immediate drop in the ventricular pressure and transmitral pressure gradient. Albeit a single real clinical case, it is our hope that such detailed engineering computational analysis could shed light on the underlying biomechanical mechanisms of TAVR impact on MR.

Author Correction: New insights into mitral heart valve prolapse after chordae rupture through fluid-structure interaction computational modeling.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Copper-Catalyzed Regio- and Enantioselective Addition of Silicon Grignard Reagents to Alkenes Activated by Azaaryl Groups.

A new application of silicon Grignard reagents in C(sp3 )-Si bond formation is reported. With the aid of BF3 ⋅OEt2 , these silicon nucleophiles add across alkenes activated by various azaaryl groups under copper catalysis. An enantioselective version employing benzoxazole-activated alkenes as substrates and a CuI-josiphos complex as catalyst has been developed, forming the C(sp3)-Si bond with good to high enantiomeric ratios (up to 97:3). The method expands the toolbox for "conjugate addition" type C(sp3 )-Si bond formation.

Mechanistic Dichotomy of Magnesium- and Zinc-Based Germanium Nucleophiles in the C(sp3 )-Ge Cross-Coupling with Alkyl Electrophiles.

Robust procedures for two mechanistically distinct C(sp3 )-Ge bond formations from alkyl electrophiles and germanium nucleophiles are reported. The germanium reagents were made available as bench-stable solutions by lithium-to-magnesium and lithium-to-zinc transmetalation, respectively. The germanium Grignard reagent reacts with various primary and secondary alkyl electrophiles by an ionic nucleophilic displacement. Conversely, the coupling of the corresponding zinc reagent requires a nickel catalyst, which then engages in radical bond formations with primary, secondary, and even tertiary alkyl bromides. Both methods avoid the regioselectivity issue of alkene hydrogermylation and enable the synthesis of a wide range of functionalized alkyl-substituted germanes.