Quantification of cerebral perfusion and cerebrovascular reserve using Turbo‐QUASAR arterial spin labeling MRI

PurposeTo compare cerebral blood flow (CBF) and cerebrovascular reserve (CVR) quantification from Turbo‐QUASAR (quantitative signal targeting with alternating radiofrequency labeling of arterial regions) arterial spin labeling (ASL) and single post‐labeling delay pseudo‐continuous ASL (PCASL).MethodsA model‐based method was developed to quantify CBF and arterial transit time (ATT) from Turbo‐QUASAR, including a correction for magnetization transfer effects caused by the repeated labeling pulses. Simulations were performed to assess the accuracy of the model‐based method. Data from an in vivo experiment conducted on a healthy cohort were retrospectively analyzed to compare the CBF and CVR (induced by acetazolamide) measurement from Turbo‐QUASAR and PCASL on the basis of global and regional differences. The quality of the two ASL data sets was examined using the coefficient of variation (CoV).ResultsThe model‐based method for Turbo‐QUASAR was accurate for CBF estimation (relative error was 8% for signal‐to‐noise ratio = 5) in simulations if the bolus duration was known. In the in vivo experiment, the mean global CVR estimated by Turbo‐QUASAR and PCASL was between 63% and 64% and not significantly different. Although global CBF values of the two ASL techniques were not significantly different, regional CBF differences were found in deep gray matter in both pre‐ and postacetazolamide conditions. The CoV of Turbo‐QUASAR data was significantly higher than PCASL.ConclusionBoth ASL techniques were effective for quantifying CBF and CVR, despite the regional differences observed. Although CBF estimated from Turbo‐QUASAR demonstrated a higher variability than PCASL, Turbo‐QUASAR offers the advantage of being able to measure and control for variation in ATT

A systematic study of the sensitivity of partial volume correction methods for the quantification of perfusion from pseudo-continuous arterial spin labeling MRI

Arterial spin labeling (ASL) MRI is a non-invasive technique for the quantification of cerebral perfusion, and pseudo-continuous arterial spin labeling (PCASL) has been recommended as the standard implementation by a recent consensus of the community. Due to the low spatial resolution of ASL images, perfusion quantification is biased by partial volume effects. Consequently, several partial volume correction (PVEc) methods have been developed to reduce the bias in gray matter (GM) perfusion quantification. The efficacy of these methods relies on both the quality of the ASL data and the accuracy of partial volume estimates. Here we systematically investigate the sensitivity of different PVEc methods to variability in both the ASL data and partial volume estimates using simulated PCASL data and in vivo PCASL data from a reproducibility study. We examined the PVEc methods in two ways: the ability to preserve spatial details and the accuracy of GM perfusion estimation. Judging by the root-mean-square error (RMSE) between simulated and estimated GM CBF, the spatially regularized method was superior in preserving spatial details compared to the linear regression method (RMSE of 1.2 vs 5.1 in simulation of GM CBF with short scale spatial variations). The linear regression method was generally less sensitive than the spatially regularized method to noise in data and errors in the partial volume estimates (RMSE 6.3 vs 23.4 for SNR = 5 simulated data), but this could be attributed to the greater smoothing introduced by the method. Analysis of a healthy cohort dataset indicates that PVEc, using either method, improves the repeatability of perfusion quantification (within-subject coefficient of variation reduced by 5% after PVEc)

BASIL: A Toolbox for Perfusion Quantification using Arterial Spin Labelling

Arterial Spin Labelling (ASL) MRI is now an established non-invasive method to quantify cerebral blood flow and is increasingly being used in a variety of neuroimaging applications. With standard ASL acquisition protocols widely available, there is a growing interest in advanced options that offer added quantitative precision and information about haemodynamics beyond perfusion. In this article we introduce the BASIL toolbox, a research tool for the analysis of ASL data included within the FMRIB Software Library (FSL) and explain its operation in a variety of typical use cases. BASIL is not offered as a clinical tool, and nor is this work intended to guide the clinical application of ASL. Built around a Bayesian model-based inference algorithm, the toolbox is designed to quantify perfusion and other haemodynamic measures, such as arterial transit times, from a variety of possible ASL input data, particularly exploiting the information available in more advanced multi-delay acquisitions. At its simplest, the BASIL toolbox offers a graphical user interface that provides the analysis options needed by most users; through command line tools, it offers more bespoke options for users needing customised analyses. As part of FSL, the toolbox exploits a range of complementary neuroimaging analysis tools so that ASL data can be easily integrated into neuroimaging studies and used alongside other modalities

Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Glenn Foundation for Medical ResearchEllison Medical FoundationJuvenile Diabetes Research Foundation InternationalUnited Mitochondrial Disease FoundationNational Institutes of Health (U.S.)National Institute of Allergy and Infectious Diseases (U.S.

miR-125b Promotes Early Germ Layer Specification through Lin28/let-7d and Preferential Differentiation of Mesoderm in Human Embryonic Stem Cells

Unlike other essential organs, the heart does not undergo tissue repair following injury. Human embryonic stem cells (hESCs) grow indefinitely in culture while maintaining the ability to differentiate into many tissues of the body. As such, they provide a unique opportunity to explore the mechanisms that control human tissue development, as well as treat diseases characterized by tissue loss, including heart failure. MicroRNAs are small, non-coding RNAs that are known to play critical roles in the regulation of gene expression. We profiled the expression of microRNAs during hESC differentiation into myocardial precursors and cardiomyocytes (CMs), and determined clusters of human microRNAs that are specifically regulated during this process. We determined that miR-125b overexpression results in upregulation of the early cardiac transcription factors, GATA4 and Nkx2-5, and accelerated progression of hESC-derived myocardial precursors to an embryonic CM phenotype. We used an in silico approach to identify Lin28 as a target of miR-125b, and validated this interaction using miR-125b knockdown. Anti-miR-125b inhibitor experiments also showed that miR-125b controls the expression of miRNA let-7d, likely through the negative regulatory effects of Lin28 on let-7. We then determined that miR-125b overexpression inhibits the expression of Nanog and Oct4 and promotes the onset of Brachyury expression, suggesting that miR-125b controls the early events of human CM differentiation by inhibiting hESC pluripotency and promoting mesodermal differentiation. These studies identified miR-125b as an important regulator of hESC differentiation in general, and the development of hESC-derived mesoderm and cardiac muscle in particular. Manipulation of miR-125b-mediated pathways may provide a novel approach to directing the differentiation of hESC-derived CMs for cell therapy applications

Reproducibility of arterial spin labeling cerebral blood flow image processing:A report of the ISMRM open science initiative for perfusion imaging (OSIPI) and the ASL MRI challenge

Purpose: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. Methods: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. Results: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. Conclusions: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.</p

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

A Novel High-Throughput Vaccinia Virus Neutralization Assay and Preexisting Immunity in Populations from Different Geographic Regions in China

Background: Pre-existing immunity to Vaccinia Tian Tan virus (VTT) resulting from a large vaccination campaign against smallpox prior to the early 1980s in China, has been a major issue for application of VTT-vector based vaccines. It is essential to establish a sensitive and high-throughput neutralization assay to understand the epidemiology of Vaccinia-specific immunity in current populations in China. Methodology/Principal Findings: A new anti-Vaccinia virus (VACV) neutralization assay that used the attenuated replication-competent VTT carrying the firefly luciferase gene of Photinus pyralis (rTV-Fluc) was established and standardized for critical parameters that included the choice of cell line, viral infection dose, and the infection time. The current study evaluated the maintenance of virus-specific immunity after smallpox vaccination by conducting a non-randomized, crosssectional analysis of antiviral antibody-mediated immune responses in volunteers examined 30–55 years after vaccination. The rTV-Fluc neutralization assay was able to detect neutralizing antibodies (NAbs) against Vaccinia virus without the ability to differentiate strains of Vaccinia virus. We showed that the neutralizing titers measured by our assay were similar to those obtained by the traditional plaque reduction neutralization test (PRNT). Using this assay, we found a low prevalence of NAb to VTT (7.6%) in individuals born before 1980 from Beijing and Anhui provinces in China, and when present, anti-VTT NAb titers were low. No NAbs were detected in all 222 samples from individuals born after 1980. There was no significan

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV