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.

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.

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.

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.

Enantioselective Construction of α-Chiral Silanes by Nickel-Catalyzed C(sp3 )-C(sp3 ) Cross-Coupling.

An enantioselective C(sp3 )-C(sp3 ) cross-coupling of racemic α-silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl2 /(S,S)-Bn-Pybox and yields α-chiral silanes with high enantiocontrol. The catalyst system does not promote the cross-coupling of the corresponding carbon analogue, corroborating the stabilizing effect of the silyl group on the alkyl radical intermediate (α-silicon effect). Both coupling partners can be, but do not need to be, functionalized, and hence, even α-chiral silanes with no functional group in direct proximity of the asymmetrically substituted carbon atom become accessible. This distinguishes the new method from established approaches for the synthesis of α-chiral silanes.

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.

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.

Simulated Transcatheter Aortic Valve Flow: Implications of Elliptical Deployment and Under-Expansion at the Aortic Annulus.

Clinical use of transcatheter aortic valves (TAVs) has been associated with abnormal deployment, including oval deployment and under-expansion when placed into calcified aortic annuli. In this study, we performed an integrated computational and experimental investigation to quantify the impact of abnormal deployment at the aortic annulus on TAV hemodynamics. A size 23 mm generic TAV computational model, developed and published previously, was subjected to elliptical deployment at the annulus with eccentricity levels up to 0.68 and to under-expansion of the TAV at the annulus by up to 25%. The hemodynamic performance was quantified for each TAV deployment configuration. TAV opening geometries were fabricated using stereolithography and then subjected to steady forward flow testing in accordance with ISO-5840. Centerline pressure profiles were compared to validate the computational model. Our findings show that slight ellipticity of the TAV may not lead to degeneration of hydrodynamic performance. However, under large ellipticity, increases in transvalvular pressure gradients were observed. Under-expanded deployment has a much greater negative effect on the TAV hemodynamics compared with elliptical deployment. The maximum turbulent viscous shear stress (TVSS) values were found to be significantly larger in under-expanded TAVs. Although the maximum value of TVSS was not large enough to cause hemolysis in all cases, it may cause platelets activation, especially for under-expanded deployments.

Numerical Parametric Study of Paravalvular Leak Following a Transcatheter Aortic Valve Deployment Into a Patient-Specific Aortic Root.

Paravalvular leak (PVL) is a relatively frequent complication after transcatheter aortic valve replacement (TAVR) with increased mortality. Currently, there is no effective method to pre-operatively predict and prevent PVL. In this study, we developed a computational model to predict the severity of PVL after TAVR. Nonlinear finite element (FE) method was used to simulate a self-expandable CoreValve deployment into a patient-specific aortic root, specified with human material properties of aortic tissues. Subsequently, computational fluid dynamics (CFD) simulations were performed using the post-TAVR geometries from the FE simulation, and a parametric investigation of the impact of the transcatheter aortic valve (TAV) skirt shape, TAV orientation, and deployment height on PVL was conducted. The predicted PVL was in good agreement with the echocardiography data. Due to the scallop shape of CoreValve skirt, the difference of PVL due to TAV orientation can be as large as 40%. Although the stent thickness is small compared to the aortic annulus size, we found that inappropriate modeling of it can lead to an underestimation of PVL up to 10 ml/beat. Moreover, the deployment height could significantly alter the extent and the distribution of regurgitant jets, which results in a change of leaking volume up to 70%. Further investigation in a large cohort of patients is warranted to verify the accuracy of our model. This study demonstrated that a rigorously developed patient-specific computational model can provide useful insights into underlying mechanisms causing PVL and potentially assist in pre-operative planning for TAVR to minimize PVL.

C-C Bond (Hetero)arylation of Ring-Fused Benzocyclobutenols and Application in the Assembly of Polycyclic Aromatic Hydrocarbons.

Herein, we disclose a new and efficient synthetic approach to triphenylene-based polycyclic aromatic hydrocarbons (PAHs) from ring-fused benzocyclobutenols (RBCBs) through the cleavage of the C-C σ-bond. Two key transformations are involved: (a) palladium-catalyzed C-C bond (hetero)arylation of RBCBs; and (b) Lewis acid-promoted intramolecular annulation leading to complex polycyclic compounds. A variety of multiply substituted triphenylenes and derivatives are obtained in synthetically useful yields.

Development of an In Vitro Model to Characterize the Effects of Transcatheter Aortic Valve on Coronary Artery Flow.

Impairment of coronary artery flow, in either acute or chronic conditions, is a severe complication of transcatheter aortic valve (TAV) implantation, which can arise due to improper TAV positioning. However, little work has been done to quantify the effects of the TAV positioning on the coronary flow. In this study, a realistic in vitro model of coronary artery flow was developed and used to investigate the impact of TAV deployed orientations on coronary flow. The coronary hemodynamics was first replicated mathematically using a lumped parameter model with time-varying myocardial resistance. Based on the analytical model, two stepper motor controlled stopcock valves were integrated in a left heart simulator to represent the variable myocardial resistance in the experimental setup. The coronary flow and pressure waveforms obtained from the in vitro system were consistent with published data. With a TAV deployed in different orientations, the measured results demonstrated that TAV orientation does not have a significant impact on the coronary flow. The developed in vitro model can be further utilized to simulate coronary flow under various pathological conditions.

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.

Survey of mycotic mastitis in dairy cows from Heilongjiang Province, China.

A survey of the prevalence rate, pathogenic subspecies, and risk factors of mycotic mastitis in dairy cows from Heilongjiang Province, China, was conducted. Milk samples from 412 cows with chronic mastitis were collected and cultured on 8 % sheep blood agar, MacConkey agar, and Sabouraud agar with chloramphenicol. Counting of the morphologically distinct colonies was performed, as well as the isolation and identification of organisms through phenotypical and physiological criteria. Four hundred seventy-eight aerobic microorganisms were isolated. Yeasts and yeast-like fungi 35.6 % (170/478) and bacteria 64.4 % (308/478) were isolated. The fungal isolates were identified as Candida (79.4 %), Trichosporon (5.9 %), Aspergillus (7.1 %), Cryptococcus (2.4 %), and Rhodotorula (4.1 %). More than ten species of yeast were isolated including Candida krusei 50/135 (37 %), Candida rugosa 16/135 (11.9 %), and Candida lusitaniae 15/135 (11.1 %). A higher positivity (18.5 and 56.3 %) (P ≤0.05) was observed in cows from environmental temperatures of 0-15 and 15-35 °C than those at <0 °C and in cows affected by the disease for >45 and 30-45 days compared with cows suffering 10-30 days. Meanwhile, a statistically significant difference (44.9 vs. 31.4 %) (P ≤0.05) was observed under extensive raising systems vs. intensive raising systems. It appears that Candida is a major pathogen of mycotic mastitis of dairy cows. Extensive raising system, high environmental temperature (15-35 °C), and the duration of the disease (>30 days) were important risk factors of the incidence of mycotic mastitis. Here, we provide a theoretical foundation for research into preventing and treating mycotic mastitis of dairy cows in China.

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.

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.

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.

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.

Anisotropic micro- and nano-capsules.

In this work, we introduce anisotropically shaped, ultrathin micro- and nano-capsules fabricated by layer-by-layer approach. The original cubic and tetrahedral shapes of the template particles were replicated to produce hollow capsules with well-defined edges. Introducing tannic acid as a component of LbL shells resulted in enhanced chemical stability of these hollow polymer structures under a wide pH range due to high pK(a) value. Computational studies demonstrated increased mechanical stability of the anisotropic capsules under osmotic pressure variation due to sharp edges and vertices acting as a reinforcing frame in contrast to spherical microcapsules that undergo random buckling.

[Comparison of prospectively electrocardiographic triggered spiral and sequential acquisition for coronary computed tomographic angiography using dual-source computed tomography].

OBJECTIVE: To compare the image quality and radiation dose of prospectively electrocardiogram (ECG) -triggered spiral and sequential acquisition for coronary computed tomographic angiography by dual-source computed tomography. METHODS: Sixty patients with suspected or known coronary artery disease were randomly divided into two groups. Group A underwent prospective ECG-triggering spiral scan and Group B underwent prospective ECG-triggering sequential scan. Both the image quality and radiation dose of the two groups were compared. RESULTS: There was no significant difference in age and body mass index of the two groups. The average image quality score was 1.12 ± 0.38 in group A and 1.14 ± 0.38 in group B (Z=-0.291,P=0.771) . The rates of diagnostic coronary segments for two groups were 98.87% and 99.56% respectively (X2=0.59,P=0.443) . The mean radiation dose of group A was significantly lower than that of group B [ (1.31 ± 0.30) mSv vs. (3.36 ± 0.93) mSv; t=11.47, P=0.000] . CONCLUSION: Compared with the prospective ECG-triggered sequential acquisition, the prospective ECG - triggered spiral scan for coronary computed tomographic angiography can remarkably reduce radiation dose without impairing image quality in patients with a low and stable heart rate (≤ 70 bpm) .