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Automated Motion Correction and 3D Vessel Centerlines Reconstruction from Non-simultaneous Angiographic Projections
© 2019, Springer Nature Switzerland AG. Automated estimation of 3D centerlines is necessary to transform angiographic projections into accurate 3D reconstructions. Although several methods exist for 3D centerline reconstruction, most of them are sensitive to the motion in coronary arteries when images are acquired by a single-plane rotational X-ray system. The objective of the proposed method is to rectify the motion-related deformations in coronary vessels from 2D projections and subsequently achieve an optimal 3D centerline reconstruction. Rigid motion in arteries is removed by estimating the optimal rigid transformation from all projection planes. The remaining non-rigid motion at end-diastole is modelled by a radial basis function based warping of 2D centerlines. Point correspondences are then generated from all projection planes by least squares matching. The final 3D centerlines are obtained by 3D non-uniform rational basis splines fitting over generated point correspondences. Experimental analysis over 20 coronary vessel trees (12 right coronary artery: RCA and 8 left coronary artery: LCA) demonstrates that the rigid transformation is able to reduce the coronary vessel movements to 0.72 mm average, while the final 3D centerline reconstruction achieves an average rms error of 0.31 mm, when backprojected on angiographic planes.
Age-Specific Associations of Renal Impairment With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Transient Ischemic Attack and Stroke.
BACKGROUND AND PURPOSE: It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small-vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age. METHODS: In a population-based study of transient ischemic attack and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and total SVD burden (total SVD score) adjusting for age, sex, vascular risk factors, and premorbid blood pressure (mean blood pressure during 15 years preevent). RESULTS: Of 1080 consecutive patients, 1028 (95.2%) had complete magnetic resonance imaging protocol and creatinine measured at baseline. Renal impairment was associated with total SVD score (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.69-2.75; P<0.001), but only at age <60 years (<60 years: OR, 3.97; 95% CI, 1.69-9.32; P=0.002; 60-79 years: OR, 1.01; 95% CI, 0.72-1.41; P=0.963; ≥80 years: OR, 0.95; 95% CI, 0.59-1.54; P=0.832). The overall association of renal impairment and total SVD score was also attenuated after adjustment for age, sex, history of hypertension, diabetes mellitus, and premorbid average systolic blood pressure (adjusted OR, 0.76; 95% CI, 0.56-1.02; P=0.067), but the independent association of renal impairment and total SVD score at age <60 years was maintained (adjusted OR, 3.11; 95% CI, 1.21-7.98; P=0.018). Associations of renal impairment and SVD were consistent for each SVD marker at age <60 years but were strongest for cerebral microbleeds (OR, 5.84; 95% CI, 1.45-23.53; P=0.013) and moderate-severe periventricular white matter hyperintensities (OR, 6.28; 95% CI, 1.54-25.63; P=0.010). CONCLUSIONS: The association of renal impairment and cerebral SVD was attenuated with adjustment for shared risk factors at older ages, but remained at younger ages, consistent with a shared susceptibility to premature disease.
Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.
BACKGROUND AND PURPOSE: In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. METHODS: In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. RESULTS: Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P<0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden (Ptrend=0.87), but the 5-year risk of ICH was steeply related (Ptrend<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden (Ptrend=0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events (Ptrend=0.007), the association with ICH was accounted for (Ptrend<0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P=0.035). CONCLUSIONS: In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.
OBJECTIVE: Since use of diffusion-weighted imaging (DWI) positivity in the "tissue-based" definition of stroke in patients with a clinical TIA is supported by the high associated 90-day risk of recurrent stroke, we aimed to determine long-term prognostic significance, stratified by etiologic subtype, and whether the same tissue-based distinction is predictive in minor strokes. METHODS: Consecutive eligible patients with TIA or minor stroke (NIH Stroke Scale [NIHSS] ≤3) in the population-based Oxford Vascular Study underwent brain MRI at baseline. Stroke risk on 10-year follow-up was stratified by NIHSS (0/1 vs 2/3) and Trial of Org 10172 in Acute Stroke Treatment classification of the initial event. RESULTS: Among 1,033 patients (633 TIA; 400 minor stroke), 248 (24.0%) had acute lesions on DWI (13.9% of TIAs; 40.0% of minor strokes). A positive DWI was associated with an increased 10-year risk of recurrent ischemic stroke after an index TIA (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.28-5.54, p = 0.009) or a stroke with NIHSS 0-1 (3.03, 1.29-7.08, p = 0.011), but not after a stroke with NIHSS 2-3 (0.70, 0.24-2.10, p = 0.53). Ischemic stroke risk after DWI-positive TIA was at least equivalent to that after DWI-negative stroke (1.81, 0.82-4.00, p = 0.14). Among all patients, DWI positivity was most predictive of 10-year risk after cryptogenic events (4.68, 1.70-12.92, p = 0.003). CONCLUSION: DWI positivity is associated with an increased long-term risk of recurrent stroke after TIA and minor stroke, supporting a tissue-based definition of minor stroke as well as TIA. Prognostic value is greatest after cryptogenic events.
Decoupling tRNA promoter and processing activities enables specific Pol-II Cas9 guide RNA expression.
Spatial/temporal control of Cas9 guide RNA expression could considerably expand the utility of CRISPR-based technologies. Current approaches based on tRNA processing offer a promising strategy but suffer from high background. Here, to address this limitation, we present a screening platform which allows simultaneous measurements of the promoter strength, 5', and 3' processing efficiencies across a library of tRNA variants. This analysis reveals that the sequence determinants underlying these activities, while overlapping, are dissociable. Rational design based on the ensuing principles allowed us to engineer an improved tRNA scaffold that enables highly specific guide RNA production from a Pol-II promoter. When benchmarked against other reported systems this tRNA scaffold is superior to most alternatives, and is equivalent in function to an optimized version of the Csy4-based guide RNA release system. The results and methods described in this manuscript enable avenues of research both in genome engineering and basic tRNA biology.
Chromatin immunoprecipitation (ChIP) is a valuable tool for the endocrine researcher, providing a means to measure the recruitment of hormone-activated nuclear receptors, for example. However, the technique can be challenging to perform and has multiple experimental steps, risking introduction of error at each. The data produced can be challenging to interpret; several different methods are commonly used for normalising data and thus comparing between conditions. Absolute, sensitive quantification of protein-bound DNA is important for correct interpretation of the data. In addition, such quantification can help the investigator in troubleshooting experiments. Here, we outline a ChIP strategy combining droplet digital PCR for accurate quantification with an internal spike-in control for normalisation. This combination strengthens the reliability of ChIP data and allows the operator to optimise their protocol with greater confidence.
[This corrects the article DOI: 10.1371/journal.pone.0172921.].
Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.
The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein-protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,6'-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,6'-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.
Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints.
In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor binding. Sasquatch performs a comprehensive k-mer-based analysis of DNase footprints to determine any k-mer's potential for protein binding in a specific cell type and how this may be changed by sequence variants. Therefore, Sasquatch uses an unbiased approach, independent of known transcription factor binding sites and motifs. Sasquatch only requires a single DNase-seq data set per cell type, from any genotype, and produces consistent predictions from data generated by different experimental procedures and at different sequence depths. Here we demonstrate the effectiveness of Sasquatch using previously validated functional SNPs and benchmark its performance against existing approaches. Sasquatch is available as a versatile webtool incorporating publicly available data, including the human ENCODE collection. Thus, Sasquatch provides a powerful tool and repository for prioritizing likely regulatory SNPs in the noncoding genome.
State-of-the-art review article. Atherosclerosis affecting fat: What can we learn by imaging perivascular adipose tissue?
Perivascular adipose tissue (PVAT) surrounding the human coronary arteries, secretes a wide range of adipocytokines affecting the biology of the adjacent vascular wall in a paracrine way. However, we have recently found that PVAT also behaves as a sensor of signals coming from the vascular wall, to which it reacts by changing its morphology and secretory profile. Indeed, vascular inflammation, a key feature of vascular disease pathogenesis, leads to the release of inflammatory signals that disseminate into local fat, inducing local lipolysis and inhibiting adipogenesis. This ability of PVAT to sense inflammatory signals from the vascular wall, can be used as a "thermometer" of the vascular wall, allowing for non-invasive detection of coronary inflammation. Vascular inflammation induces a shift of PVAT's composition from lipid to aqueous phase, resulting into increased computed tomography (CT) attenuation around the inflamed artery, forming a gradient with increasing attenuation closer to the inflamed coronary artery wall. These spatial changes in PVAT's attenuation are easily detected around culprit lesions during acute coronary syndromes. A new biomarker designed to captured these spatial changes in PVAT's attenuation around the human coronary arteries, the Fat Attenuation Index (FAI), has additional predictive value in stable patients for cardiac mortality and non-fatal heart attacks, above the prediction provided by the current state of the art that includes risk factors, calcium score and presence of high risk plaque features. The use of perivascular FAI in clinical practice may change the way we interpret cardiovascular CT angiography, as it is applicable to any coronary CT angiogram, and it offers dynamic information about the inflammatory burden of the coronary arteries, providing potential guidance for preventive measures and invasive treatments.
Excessive consumption of free sugars (which typically includes a composite of glucose and fructose) is associated with an increased risk of developing chronic metabolic diseases including obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and cardiovascular disease. Determining the utilisation, storage and fate of dietary sugars in metabolically relevant tissues is fundamental to understanding their contribution to metabolic disease risk. To date, the study of fructose metabolism has primarily focussed on the liver, where it has been implicated in impaired insulin sensitivity, increased fat accumulation and dyslipidaemia. Yet we still have only a limited understanding of the mechanisms by which consumption of fructose, as part of a mixed meal, may alter hepatic fatty acid synthesis and partitioning. Moreover, surprisingly little is known about the metabolism of fructose within other organs, specifically subcutaneous adipose tissue, given that it is the largest metabolically active organ in the human body and is consistently exposed to nutrient fluxes. This review summarises what is known about fructose metabolism in the liver and adipose tissue and examines evidence for tissue-specific and sex-specific responses to fructose. High fructose intake, through consumption of sugar-rich foods, can increase the process of de novo lipogenesis (DNL) within the liver. This leads to an increase in intrahepatic triacylglycerol (TAG) accumulation and/or increased secretion of very low-density lipoproteins resulting in elevated plasma TAG concentrations. The increase in intrahepatic TAG is associated with a higher risk of insulin resistance, type 2 diabetes and cardiovascular disease. Over consumption of fructose has also been shown to increase visceral adipose tissue mass however the effect fructose has on subcutaneous adipose tissue remains to be determined.2 This article is protected by copyright. All rights reserved.
Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements.
Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.
CLINICAL QUESTION:Is transfusing red cell components using a restrictive transfusion threshold (Hb < 75 g L-1 ) as safe as a liberal transfusion threshold (Hb < 95 g L-1 in intensive care and < 85 g L-1 outside intensive care) during and after cardiac surgery for adults at moderate to high risk of death? EVIDENCE FROM TRIAL:In adults undergoing cardiac surgery who were at moderate to high risk for death, using a restrictive red-cell transfusion threshold was as safe as a liberal red cell transfusion threshold (composite outcome of death from any cause, myocardial infarction, stroke or new-onset renal failure with dialysis at 6 months after surgery).
Quantifying T<sub>2</sub> relaxation time changes within lesions defined by apparent diffusion coefficient in grey and white matter in acute stroke patients.
Apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia highlighting a lesion in acute stroke patients. The MRI T2 relaxation time changes in ischaemic brain such that T2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 hours of symptom onset and scanned at 3T for 3D T1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T2 images, respectively. T2 changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms/hour in the whole, GM and WM lesions, respectively. Thus, T2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.
Non-alcoholic fatty liver disease encompasses a spectrum of conditions from hepatic steatosis through to cirrhosis; obesity is a known risk factor. The liver plays a major role in regulating fatty acid metabolism and perturbations in intrahepatic processes have potential to impact on metabolic health. It remains unclear why intra-hepatocellular fat starts to accumulate, but it likely involves an imbalance between fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver and TAG export from the liver. As man spends the majority of the day in a postprandial rather than postabsorptive state, dietary fatty acid intake should be taken into consideration when investigating why intra-hepatic fat starts to accumulate. This review will discuss the impact of the quantity and quality of dietary fatty acids on liver fat accumulation and metabolism, along with some of the potential mechanisms involved. Studies investigating the role of dietary fat in liver fat accumulation, although surprisingly limited, have clearly demonstrated that it is total energy intake, rather than fat intake per se, that is a key mediator of liver fat content; hyperenergetic diets increase liver fat whilst hypoenergetic diets decrease liver fat content irrespective of total fat content. Moreover, there is now, albeit limited evidence emerging to suggest the composition of dietary fat may also play a role in liver fat accumulation, with diets enriched in saturated fat appearing to increase liver fat content to a greater extent when compared with diets enriched in unsaturated fats.
Acceleration of vessel-selective dynamic MR Angiography by pseudocontinuous arterial spin labeling in combination with Acquisition of ConTRol and labEled images in the Same Shot (ACTRESS).
PURPOSE: The recently introduced "Acquisition of ConTRol and labEled imaging in the Same Shot" (ACTRESS) approach was designed to halve the scan time of arterial spin labeling (ASL) -based 4D-MRA by obtaining both labeled and control images in a single Look-Locker readout. However, application for vessel-selective labeling remains difficult. The aim of this study was to achieve a combination of ACTRESS and vessel-selective labeling to halve the scan time of vessel-selective 4D-MRA. METHODS: By Bloch equation simulations, Look-Locker pseudocontinuous-ASL (pCASL) was optimized to achieve constant static tissue signal across the multidelay readout, which is essential for the ACTRESS approach. Additionally, a new subtraction scheme was proposed to achieve visualization of the inflow phase even when labeled blood will have already arrived in the distal arteries during the first phase acquisition due to the long duration of the pCASL labeling module. In vivo studies were performed to investigate the signal variation of the static tissue, as well as to assess image quality of vessel-selective 4D-MRA with ACTRESS. RESULTS: In in vivo studies, the mean signal variation of the static tissue was 8.98% over the Look-Locker phases, thereby minimizing the elevation of background signal. This allowed visualization of peripheral arteries and slowly arriving arterial blood with image quality as good as conventional pCASL within half the acquisition time. Vessel-selective pCASL-ACTRESS enabled the separated visualization of vessels arising from internal and external carotid arteries within this shortened acquisition time. CONCLUSION: By combining vessel-selective pCASL and ACTRESS approach, 4D-MRA of a single targeted arterial tree was achieved in a few minutes.
© 2013 by Apple Academic Press, Inc. Epigenetic regulation of gene expression is a dynamic mechanism, which permits precise regulation throughout differentiation . It plays a crucial role in preserving the hierarchical structure of tissues and is involved in maintaining stemness and fate determination of adult stem cells [2, 3]. Indeed, DNA methylation varies throughout cell differentiation  and epigenetic control is required for the multipotency of hematopoietic stem cells .