Radiotherapy-activated NBTXR3 nanoparticles promote ferroptosis through induction of lysosomal membrane permeabilization.

PURPOSE: Radiotherapy-activated NBTXR3 (NBTXR3 + RT) has demonstrated superior efficacy in cancer cell destruction and tumor growth control, compared to radiotherapy (RT), in preclinical and clinical settings. Previous studies highlighted the immunomodulatory properties of NBTXR3 + RT, such as modification of tumor cell immunogenicity/adjuvanticity, producing an effective local tumor control and abscopal effect, related to an enhanced antitumor immune response. Furthermore, NBTXR3 + RT has shown potential in restoring anti-PD1 efficacy in a refractory tumor model. However, the early events leading to these results, such as NBTXR3 endocytosis, intracellular trafficking and primary biological responses induced by NBTXR3 + RT remain poorly understood. METHODS: We analyzed by transmission electron microscopy endocytosis and intracellular localization of NBTXR3 nanoparticles after endocytosis in various cell lines, in vitro and in vivo. A kinetic of NBTXR3 endocytosis and its impact on lysosomes was conducted using LysoTracker staining, and a RNAseq analysis was performed. We investigated the ability of NBTXR3 + RT to induce lysosomal membrane permeabilization (LMP) and ferroptosis by analyzing lipid peroxidation. Additionally, we evaluated the recapture by cancer cells of NBTXR3 released from dead cells. RESULTS: NBTXR3 nanoparticles were rapidly internalized by cells mainly through macropinocytosis and in a less extend by clathrin-dependent endocytosis. NBTXR3-containing endosomes were then fused with lysosomes. The day following NBTXR3 addition, we measured a significant increase in LysoTracker lysosome labeling intensity, in vitro as in vivo. Following RT, a significant lysosomal membrane permeabilization (LMP) was measured exclusively in cells treated with NBTXR3 + RT, while RT had no effect. The day post-irradiation, a significant increase in lipid peroxidation, a biomarker of ferroptosis, was measured with NBTXR3 + RT compared to RT. Moreover, we demonstrated that NBTXR3 nanoparticles released from dead cells can be recaptured by cancer cells. CONCLUSIONS: Our findings provide novel insights into the early and specific biological effects induced by NBTXR3 + RT, especially LMP, not induced by RT in our models. The subsequent significant increase in lipid peroxidation partially explains the enhanced cancer cell killing capacity of NBTXR3 + RT compared to RT, potentially by promoting ferroptosis. This study improves our understanding of the cellular mechanisms underlying NBTXR3 + RT and highlights its potential as an agnostic therapeutic strategy for solid cancers treatment.

A Comparison of Devices for Race Day Characterization of North American Turfgrass Thoroughbred Racing Surfaces.

Both pre-race meet and daily turf surface condition measurements are required by regulations adopted as part of the Horseracing Integrity and Safety Act (HISA). The Orono Biomechanical Surface Tester (OBST) is the primary device used for characterizing a racing surface and is used for the pre-meet inspections. Tools that are better suited for the daily testing of turf surfaces are also needed to meet the new federal regulations. The purpose of this study was to compare five simple tools commonly used in turf applications to the OBST. Data were collected with each of the six devices at plots chosen to approximate the current and potential compositions of North American turf racetracks. Correlations and linear regression models were then established between the simple tool measurements and the parameters measured by the OBST. The moisture probe was found to be the primary device for race day characterization due to its strong correlation to OBST measurements. The Longchamp Penetrometer is also prioritized for daily measurements due to its established correlation to horse performance and injuries. The Clegg Impact Hammer provides further improvement of the linear regression model. The Turf Shear Tester and GoingStick® were not found to correlate well to the biomechanically based device.

Breath Biomarkers of Influenza Infection.

Background: Volatile organic compounds (VOCs) are produced systemically due to varied physiological states such as oxidative stress and are excreted through the lungs. Benchtop and preliminary clinical data suggest that breath testing may be a useful diagnostic modality for viral respiratory tract infections. Methods: Patients with influenza-like illness (ILI) presenting to a single clinic in San Antonio, Texas, from 3/2017 to 3/2019 submitted a 2-minute breath sample in addition to a nasopharyngeal swab collected for polymerase chain reaction (PCR) assay for respiratory pathogens. VOCs were assayed with gas chromatography-mass spectrometry (GC-MS), and data were analyzed to identify breath VOC biomarkers that discriminated between ILI patients with and without a polymerase chain reaction (PCR) assay that was positive for influenza. Results: Demographic, clinical, PCR, and breath data were available for 237 episodes of ILI, among which 32 episodes (13.5%) were PCR positive for influenza. Twenty candidate VOCs identified patients with influenza with greater than random accuracy. A predictive algorithm using 4 candidate biomarkers identified this group with 78% accuracy (74% sensitivity, 70% specificity). Based on their mass spectra, most of these biomarkers were n-alkane derivatives, consistent with products of oxidative stress. Conclusions: A breath test for VOC biomarkers accurately identified ILI patients with PCR-proven influenza. These findings bolster those of others that a rapid, accurate, universal point-of-care influenza diagnostic test based on assay of exhaled-breath VOCs may be feasible. The next step will be a study of patients with ILI using a simplified method of breath collection that would facilitate translation for use in clinical practice.

Breath biomarkers of total body irradiation in non-human primates.

Background.Radiation exposure causes oxidative stress, eliciting production of metabolites that are exhaled in the breath as volatile organic compounds (VOCs). We evaluated breath VOCs as potential biomarkers for use in radiation biodosimetry.Methods.Five anesthetized non-human primates receive total body irradiation (TBI) of three daily fractions of 120 cGy per day for three days, resulting in a cumulative dose of 10.8 Gy. Breath samples were collected prior to irradiation and after each radiation fraction, and analyzed with gas chromatography mass spectrometry.Results.TBI elicited a prompt and statistically significant increase in the abundance of several hundred VOCs in the breath, including some that were increased more than five-fold, with100% sensitivity and 100% specificity for radiation exposure. The most significant breath VOC biomarkers of radiation mainly comprised straight-chain n-alkanes (e.g. hexane), as well as methylated alkanes (e.g. 3-methyl-pentane) and alkane derivatives (e.g. 2-butyl-1-octanol), consistent with metabolic products of oxidative stress. An unidentified breath VOC biomarker increased more than ten-fold following TBI, and rose linearly with the total cumulative dose of radiation (R2= 0.92).Conclusions.TBI of non-human primates elicited increased production of breath VOCs consistent with increased oxidative stress. These findings provide a rational basis for further evaluation of breath VOC biomarkers in human radiation biodosimetry.

An Experimental Comparison of Simple Measurements Used for the Characterization of Sand Equestrian Surfaces.

Quantitative measurements of performance parameters have the potential to increase consistency and enhance performance of the surfaces as well as to contribute to the safety of horses and riders. This study investigates how factors known to influence the performance of the surface, incorporation of a drainage package, control of the moisture control, and introduction of a geotextile reinforcement, affect quantitative measurements of arena materials. The measurements are made by using affordable lightweight testing tools which are readily available or easily constructed. Sixteen boxes with arena materials at a consistent depth were tested with the Going Stick (GS), both penetration resistance and shear, the impact test device (ITD), and the rotational peak shear device (RPS). Volumetric moisture content (VMC %) was also tested with time-domain reflectometry (TDR). Results obtained using GS, RPS, ITD, and TDR indicate that the presence of the drainage package, moisture content, and geotextile addition were detected. Alterations due to combinations of treatments could also be detected by GS, ITD, and TDR. While the testing showed some limitations of these devices, the potential exists to utilize them for quality control of new installations as well as for the monitoring of maintenance of the surfaces.

Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.

There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short-lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron-muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP-43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti-TDP-43 aggregation effect was also confirmed in a cell line expressing TDP-43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

How Computational Experiments Can Improve Our Understanding of the Genetic Architecture of Common Human Diseases.

Susceptibility to common human diseases such as cancer is influenced by many genetic and environmental factors that work together in a complex manner. The state of the art is to perform a genome-wide association study (GWAS) that measures millions of single-nucleotide polymorphisms (SNPs) throughout the genome followed by a one-SNP-at-a-time statistical analysis to detect univariate associations. This approach has identified thousands of genetic risk factors for hundreds of diseases. However, the genetic risk factors detected have very small effect sizes and collectively explain very little of the overall heritability of the disease. Nonetheless, it is assumed that the genetic component of risk is due to many independent risk factors that contribute additively. The fact that many genetic risk factors with small effects can be detected is taken as evidence to support this notion. It is our working hypothesis that the genetic architecture of common diseases is partly driven by non-additive interactions. To test this hypothesis, we developed a heuristic simulation-based method for conducting experiments about the complexity of genetic architecture. We show that a genetic architecture driven by complex interactions is highly consistent with the magnitude and distribution of univariate effects seen in real data. We compare our results with measures of univariate and interaction effects from two large-scale GWASs of sporadic breast cancer and find evidence to support our hypothesis that is consistent with the results of our computational experiment.

Benchmarking relief-based feature selection methods for bioinformatics data mining.

Modern biomedical data mining requires feature selection methods that can (1) be applied to large scale feature spaces (e.g. 'omics' data), (2) function in noisy problems, (3) detect complex patterns of association (e.g. gene-gene interactions), (4) be flexibly adapted to various problem domains and data types (e.g. genetic variants, gene expression, and clinical data) and (5) are computationally tractable. To that end, this work examines a set of filter-style feature selection algorithms inspired by the 'Relief' algorithm, i.e. Relief-Based algorithms (RBAs). We implement and expand these RBAs in an open source framework called ReBATE (Relief-Based Algorithm Training Environment). We apply a comprehensive genetic simulation study comparing existing RBAs, a proposed RBA called MultiSURF, and other established feature selection methods, over a variety of problems. The results of this study (1) support the assertion that RBAs are particularly flexible, efficient, and powerful feature selection methods that differentiate relevant features having univariate, multivariate, epistatic, or heterogeneous associations, (2) confirm the efficacy of expansions for classification vs. regression, discrete vs. continuous features, missing data, multiple classes, or class imbalance, (3) identify previously unknown limitations of specific RBAs, and (4) suggest that while MultiSURF∗ performs best for explicitly identifying pure 2-way interactions, MultiSURF yields the most reliable feature selection performance across a wide range of problem types.

To Be Immortal, Do Good or Evil.

Many people believe in immortality, but who is perceived to live on and how exactly do they live on? Seven studies reveal that good- and evil-doers are perceived to possess more immortality-albeit different kinds. Good-doers have "transcendent" immortality, with their souls persisting beyond space and time; evil-doers have "trapped" immortality, with their souls persisting on Earth, bound to a physical location. Studies 1 to 4 reveal bidirectional links between perceptions of morality and type of immortality. Studies 5 to 7 reveal how these links explain paranormal perceptions. People generally tie paranormal events to evil spirits (Study 5), but this depends upon location: Evil spirits are perceived to haunt houses and dense forests, whereas good spirits are perceived in expansive locations such as mountaintops (Study 6). However, even good spirits may be seen as trapped on Earth given extenuating circumstances (Study 7). Materials include a scale for measuring trapped and transcendent immorality.

A heuristic method for simulating open-data of arbitrary complexity that can be used to compare and evaluate machine learning methods.

A central challenge of developing and evaluating artificial intelligence and machine learning methods for regression and classification is access to data that illuminates the strengths and weaknesses of different methods. Open data plays an important role in this process by making it easy for computational researchers to easily access real data for this purpose. Genomics has in some examples taken a leading role in the open data effort starting with DNA microarrays. While real data from experimental and observational studies is necessary for developing computational methods it is not sufficient. This is because it is not possible to know what the ground truth is in real data. This must be accompanied by simulated data where that balance between signal and noise is known and can be directly evaluated. Unfortunately, there is a lack of methods and software for simulating data with the kind of complexity found in real biological and biomedical systems. We present here the Heuristic Identification of Biological Architectures for simulating Complex Hierarchical Interactions (HIBACHI) method and prototype software for simulating complex biological and biomedical data. Further, we introduce new methods for developing simulation models that generate data that specifically allows discrimination between different machine learning methods.

Uniaxial 2D Superlattice of Fe4 Molecular Magnets on Graphene.

We demonstrate that electrospray deposition enables the fabrication of highly periodic self-assembled arrays of Fe4H single molecule magnets on graphene/Ir(111). The energetic positions of molecular states are probed by means of scanning tunneling spectroscopy, showing pronounced long- and short-ranged spatial modulations, indicating the presence of both locally varying intermolecular as well as adsorption-site dependent molecule-substrate interactions. From the magnetic field dependence of the X-ray magnetic circular dichroism signal, we infer that the magnetic easy axis of each Fe4H molecule is oriented perpendicular to the sample surface and that after the deposition the value of the uniaxial anisotropy is identical to the one in bulk. Our findings therefore suggest that the observed interaction of the molecules with their surrounding does not modify the molecular magnetism, resulting in a two-dimensional array of molecular magnets that retain their bulk magnetic properties.

Correction: Cerebral Hemodynamics in Patients with Hemolytic Uremic Syndrome Assessed by Susceptibility Weighted Imaging and Four-Dimensional Non-Contrast MR Angiography.

[This corrects the article DOI: 10.1371/journal.pone.0164863.].

Non-contrast-enhanced MR angiography in critical limb ischemia: performance of quiescent-interval single-shot (QISS) and TSE-based subtraction techniques.

PURPOSE: The aim of this study was to evaluate diagnostic performance of non-contrast-enhanced 2D quiescent-interval single-shot (QISS) and 3D turbo spin-echo (TSE)-based subtraction magnetic resonance angiography (MRA) in the assessment of peripheral arteries in patients with critical limb ischemia (CLI). MATERIALS AND METHODS: Nineteen consecutive patients (74 % male, 72.8 ± 9.9 years) with CLI underwent 2D QISS and 3D TSE-based subtraction MRA at 1.5 T. Axial-overlapping QISS MRA (3 mm/2 mm; 1 × 1 mm2) covered from the toes to the aortic bifurcation while coronal 3D TSE-based subtraction MRA (1.3 × 1.2 × 1.3 mm3) was restricted to the calf only. MRA data sets (two readers) were evaluated for stenosis (≥50 %) and image quality. Results were compared with digital subtraction angiography (DSA). RESULTS: Two hundred and sixty-seven (267) segments were available for MRA-DSA comparison, with a prevalence of stenosis ≥50 % of 41.9 %. QISS MRA was rated as good to excellent in 79.5-96.0 % of segments without any nondiagnostic segments; 89.8-96.1 % of segments in 3D TSE-based subtraction MRA were rated as nondiagnostic or poor. QISS MRA sensitivities and specificities (segmental) were 92 % and 95 %, respectively, for reader one and 81-97 % for reader two. Due to poor image quality of 3D TSE-based subtraction MRA, diagnostic performance measures were not calculated. CONCLUSION: QISS MRA demonstrates excellent diagnostic performance and higher robustness than 3D TSE-based subtraction MRA in the challenging patient population with CLI. KEY POINTS: • QISS MRA allows reliable diagnosis of peripheral artery stenosis in critical limb ischemia. • Robustness of TSE-based subtraction MRA is limited in critical limb ischemia. • QISS MRA allows robust therapy planning in PAD patients with resting leg pain.

Cerebral Hemodynamics in Patients with Hemolytic Uremic Syndrome Assessed by Susceptibility Weighted Imaging and Four-Dimensional Non-Contrast MR Angiography.

BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) of patients with hemolytic uremic syndrome (HUS) and neurological symptoms performed during an epidemic outbreak of Escherichia coli O104:H4 in Northern Europe has previously shown pathological changes in only approximately 50% of patients. In contrast, susceptibility-weighted imaging (SWI) revealed a loss of venous contrast in a large number of patients. We hypothesized that this observation may be due to an increase in cerebral blood flow (CBF) and aimed to identify a plausible cause. MATERIALS AND METHODS: Baseline 1.5T MRI scans of 36 patients (female, 26; male, 10; mean age, 38.2±19.3 years) were evaluated. Venous contrast was rated on standard SWI minimum intensity projections. A prototype four-dimensional (time resolved) magnetic resonance angiography (4D MRA) assessed cerebral hemodynamics by global time-to-peak (TTP), as a surrogate marker for CBF. Clinical parameters studied were hemoglobin, hematocrit, creatinine, urea levels, blood pressure, heart rate, and end-tidal CO2. RESULTS: SWI venous contrast was abnormally low in 33 of 36 patients. TTP ranged from 3.7 to 10.2 frames (mean, 7.9 ± 1.4). Hemoglobin at the time of MRI (n = 35) was decreased in all patients (range, 5.0 to 12.6 g/dL; mean, 8.2 ± 1.4); hematocrit (n = 33) was abnormally low in all but a single patient (range, 14.3 to 37.2%; mean, 23.7 ± 4.2). Creatinine was abnormally high in 30 of 36 patients (83%) (range, 0.8 to 9.7; mean, 3.7 ± 2.2). SWI venous contrast correlated significantly with hemoglobin (r = 0.52, P = 0.0015), hematocrit (r = 0.65, P < 0.001), and TTP (r = 0.35, P = 0.036). No correlation of SWI with blood pressure, heart rate, end-tidal CO2, creatinine, and urea level was observed. Findings suggest that the loss of venous contrast is related to an increase in CBF secondary to severe anemia related to HUS. SWI contrast of patients with pathological conventional MRI findings was significantly lower compared to patients with normal MRI (mean SWI score, 1.41 and 2.05, respectively; P = 0.04). In patients with abnormal conventional MRI, mean TTP (7.45), mean hemoglobin (7.65), and mean hematocrit (22.0) were lower compared to patients with normal conventional MRI scans (mean TTP = 8.28, mean hemoglobin = 8.63, mean hematocrit = 25.23). CONCLUSION: In contrast to conventional MRI, almost all patients showed pathological changes in cerebral hemodynamics assessed by SWI and 4D MRA. Loss of venous contrast on SWI is most likely the result of an increase in CBF and may be related to the acute onset of anemia. Future studies will be needed to assess a possible therapeutic effect of blood transfusions in patients with HUS and neurological symptoms.

Optimization of 4D vessel-selective arterial spin labeling angiography using balanced steady-state free precession and vessel-encoding.

Vessel-selective dynamic angiograms provide a wealth of useful information about the anatomical and functional status of arteries, including information about collateral flow and blood supply to lesions. Conventional x-ray techniques are invasive and carry some risks to the patient, so non-invasive alternatives are desirable. Previously, non-contrast dynamic MRI angiograms based on arterial spin labeling (ASL) have been demonstrated using both spoiled gradient echo (SPGR) and balanced steady-state free precession (bSSFP) readout modules, but no direct comparison has been made, and bSSFP optimization over a long readout period has not been fully explored. In this study bSSFP and SPGR are theoretically and experimentally compared for dynamic ASL angiography. Unlike SPGR, bSSFP was found to have a very low ASL signal attenuation rate, even when a relatively large flip angle and short repetition time were used, leading to a threefold improvement in the measured signal-to-noise ratio (SNR) efficiency compared with SPGR. For vessel-selective applications, SNR efficiency can be further improved over single-artery labeling methods by using a vessel-encoded pseudo-continuous ASL (VEPCASL) approach. The combination of a VEPCASL preparation with a time-resolved bSSFP readout allowed the generation of four-dimensional (4D; time-resolved three-dimensional, 3D) vessel-selective cerebral angiograms in healthy volunteers with 59 ms temporal resolution. Good quality 4D angiograms were obtained in all subjects, providing comparable structural information to 3D time-of-flight images, as well as dynamic information and vessel selectivity, which was shown to be high. A rapid 1.5 min dynamic two-dimensional version of the sequence yielded similar image features and would be suitable for a busy clinical protocol. Preliminary experiments with bSSFP that included the extracranial vessels showed signal loss in regions of poor magnetic field homogeneity. However, for intracranial vessel-selective angiography, the proposed bSSFP VEPCASL sequence is highly SNR efficient and could provide useful information in a range of cerebrovascular diseases. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Highly Ordered Surface Self-Assembly of Fe4 Single Molecule Magnets.

Single molecule magnets (SMMs) have attracted considerable attention due to low-temperature magnetic hysteresis and fascinating quantum effects. The investigation of these properties requires the possibility to deposit well-defined monolayers or spatially isolated molecules within a well-controlled adsorption geometry. Here we present a successful fabrication of self-organized arrays of Fe4 SMMs on hexagonal boron nitride (h-BN) on Rh(111) as template. Using a rational design of the ligand shell optimized for surface assembly and electrospray as a gentle deposition method, we demonstrate how to obtain ordered arrays of molecules forming perfect hexagonal superlattices of tunable size, from small islands to an almost perfect monolayer. High-resolution low temperature scanning tunneling microscopy (STM) reveals that the Fe4 molecule adsorbs on the substrate in a flat geometry, meaning that its magnetic easy axis is perpendicular to the surface. By scanning tunneling spectroscopy (STS) and density functional theory (DFT) calculations, we infer that the majority- and minority-spin components of the spin-split lowest unoccupied molecular orbital (LUMO) can be addressed separately on a submolecular level.

Highly undersampled peripheral Time-of-Flight magnetic resonance angiography: optimized data acquisition and iterative image reconstruction.

OBJECT: The aim of this study was to investigate the acceleration of peripheral Time-of-Flight magnetic resonance angiography using Compressed Sensing and parallel magnetic resonance imaging (MRI) while preserving image quality and vascular contrast. MATERIALS AND METHODS: An analytical sampling pattern is proposed that combines aspects of parallel MRI and Compressed Sensing. It is used in combination with a dedicated Split Bregman algorithm. This approach is compared with current state-of-the-art patterns and reconstruction algorithms. RESULTS: The acquisition time was reduced from 30 to 2.5 min in a study using ten volunteer data sets, while showing improved sharpness, better contrast and higher accuracy compared to state-of-the-art techniques. CONCLUSION: This study showed the benefits of the proposed dedicated analytical sampling pattern and Split Bregman algorithm for optimizing the Compressed Sensing reconstruction of highly accelerated peripheral Time-of-Flight data.

Highly undersampled contrast-enhanced MRA with iterative reconstruction: Integration in a clinical setting.

PURPOSE: To integrate, optimize, and evaluate a three-dimensional (3D) contrast-enhanced sparse MRA technique with iterative reconstruction on a standard clinical MR system. METHODS: Data were acquired using a highly undersampled Cartesian spiral phyllotaxis sampling pattern and reconstructed directly on the MR system with an iterative SENSE technique. Undersampling, regularization, and number of iterations of the reconstruction were optimized and validated based on phantom experiments and patient data. Sparse MRA of the whole head (field of view: 265 × 232 × 179 mm(3) ) was investigated in 10 patient examinations. RESULTS: High-quality images with 30-fold undersampling, resulting in 0.7 mm isotropic resolution within 10 s acquisition, were obtained. After optimization of the regularization factor and of the number of iterations of the reconstruction, it was possible to reconstruct images with excellent quality within six minutes per 3D volume. Initial results of sparse contrast-enhanced MRA (CEMRA) in 10 patients demonstrated high-quality whole-head first-pass MRA for both the arterial and venous contrast phases. CONCLUSION: While sparse MRI techniques have not yet reached clinical routine, this study demonstrates the technical feasibility of high-quality sparse CEMRA of the whole head in a clinical setting. Sparse CEMRA has the potential to become a viable alternative where conventional CEMRA is too slow or does not provide sufficient spatial resolution.

Multi-dimensional flow-preserving compressed sensing (MuFloCoS) for time-resolved velocity-encoded phase contrast MRI.

4-D time-resolved velocity-encoded phase-contrast MRI (4-D PCI) is a fully non-invasive technique to assess hemodynamics in vivo with a broad range of potential applications in multiple cardiovascular diseases. It is capable of providing quantitative flow values and anatomical information simultaneously. The long acquisition time, however, still inhibits its wider clinical use. Acceleration is achieved at present using parallel MRI (pMRI) techniques which can lead to substantial loss of image quality for higher acceleration factors. Both the high-dimensionality and the significant degree of spatio-temporal correlation in 4-D PCI render it ideally suited for recently proposed compressed sensing (CS) techniques. We propose the Multi-Dimensional Flow-preserving Compressed Sensing (MuFloCoS) method to exploit these properties. A multi-dimensional iterative reconstruction is combined with an interleaved sampling pattern (I-VT), an adaptive masked and weighted temporal regularization (TMW) and fully automatically obtained vessel-masks. The performance of the novel method was analyzed concerning image quality, feasibility of acceleration factors up to 15, quantitative flow values and diagnostic accuracy in phantom experiments and an in vivo carotid study with 18 volunteers. Comparison with iterative state-of-the-art methods revealed significant improvements using the new method, the temporal normalized root mean square error of the peak velocity was reduced by 45.32% for the novel MuFloCoS method with acceleration factor 9. The method was furthermore applied to two patient cases with diagnosed high-grade stenosis of the ICA, which confirmed the performance of MuFloCoS to produce valuable results in the presence of pathological findings in 56 s instead of over 8 min (full sampling).

The science of style: in fashion, colors should match only moderately.

Fashion is an essential part of human experience and an industry worth over $1.7 trillion. Important choices such as hiring or dating someone are often based on the clothing people wear, and yet we understand almost nothing about the objective features that make an outfit fashionable. In this study, we provide an empirical approach to this key aesthetic domain, examining the link between color coordination and fashionableness. Studies reveal a robust quadratic effect, such that that maximum fashionableness is attained when outfits are neither too coordinated nor too different. In other words, fashionable outfits are those that are moderately matched, not those that are ultra-matched ("matchy-matchy") or zero-matched ("clashing"). This balance of extremes supports a broader hypothesis regarding aesthetic preferences-the Goldilocks principle--that seeks to balance simplicity and complexity.