For pharmacokinetic modeling of tissue physiology, there is great interest in measuring the arterial input function (AIF) from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) using paramagnetic contrast agents. Due to relaxation effects, the measured signal is a nonlinear function of the injected contrast agent concentration and depends on sequence parameters, system calibration, and time-of-flight effects, making it difficult to accurately measure the AIF during the first pass. Paramagnetic contrast agents also affect susceptibility and modify the magnetic field in proportion to their concentration. This information is contained in the MR signal phase which is discarded in a typical image reconstruction. However, quantifying AIF through contrast agent susceptibility induced phase changes is made difficult by the fact that the induced magnetic field is nonlocal and depends upon the contrast agent spatial distribution and thus on organ and vessel shapes. In this article, the contrast agent susceptibility was quantified through inversion of magnetic field shifts using a piece-wise constant model. Its feasibility is demonstrated by a determination of the AIF from the susceptibility-induced field changes of an intravenous bolus. After in vitro validation, a time-resolved two-dimensional (2D) gradient echo scan, triggered to diastole, was performed in vivo on the aortic arch during a bolus injection of 0.1 mmol/kg Gd-DTPA. An approximate geometrical model of the aortic arch constructed from the magnitude images was used to calculate the spatial variation of the field associated with the bolus. In 14 subjects, Gd concentration curves were measured dynamically (one measurement per heart beat) and indirectly validated by independent 2D cine phase contrast flow rate measurements. Flow rate measurements using indicator conservation with this novel quantitative susceptibility imaging technique were found to be in good agreement with those obtained from the cine phase contrast measurements in all subjects. Contrary to techniques that rely on intensity, the accuracy of this signal phase based method is insensitive to factors influencing signal intensity such as flip angle, coil sensitivity, relaxation changes, and time-of-flight effects extending the range of pulse sequences and contrast doses for which quantitative DCE-MRI can be applied.

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Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir proteinindependent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.

The conserved yeast histone methyltransferase Set1 targets H3 lysine 4 (H3K4) for mono, di, and trimethylation and is linked to active transcription due to the euchromatic distribution of these methyl marks and the recruitment of Set1 during transcription. However, loss of Set1 results in increased expression of multiple classes of genes, including genes adjacent to telomeres and middle sporulation genes, which are repressed under normal growth conditions because they function in meiotic progression and spore formation. The mechanisms underlying Set1-mediated gene repression are varied, and still unclear in some cases, although repression has been linked to both direct and indirect action of Set1, associated with noncoding transcription, and is often dependent on the H3K4me2 mark. We show that Set1, and particularly the H3K4me2 mark, are implicated in repression of a subset of middle sporulation genes during vegetative growth. In the absence of Set1, there is loss of the DNA-binding transcriptional regulator Sum1 and the associated histone deacetylase Hst1 from chromatin in a locus-specific manner. This is linked to increased H4K5ac at these loci and aberrant middle gene expression. These data indicate that, in addition to DNA sequence, histone modification status also contributes to proper localization of Sum1. Our results also show that the role for Set1 in middle gene expression control diverges as cells receive signals to undergo meiosis. Overall, this work dissects an unexplored role for Set1 in gene-specific repression, and provides important insights into a new mechanism associated with the control of gene expression linked to meiotic differentiation.

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Blood suppression in the lower extremities using flow-reliant methods such as double inversion recovery may be problematic due to slow blood flow. T 2 mapping using fast spin echo (FSE) acquisition was utilized to quantitate the effectiveness of double inversion recovery blood suppression in 13 subjects and showed that 25 6 12% of perceived vessel wall pixels in the popliteal arteries contained artifactual blood signal. To overcome this problem, a flow-insensitive T 2 -prepared inversion recovery sequence was implemented and optimal timing parameters were calculated for FSE acquisition. Black blood vessel wall imaging of the popliteal and femoral arteries was performed using two-dimensional T 2 -prepared inversion recovery-FSE in the same 13 subjects. Comparison with twodimensional double inversion recovery-FSE showed that T 2 -prepared inversion recovery-FSE reduced wall-mimicking blood artifacts that inflated double inversion recovery-FSE vessel wall area measurements in the popliteal artery. Key words: black blood; vessel wall imaging; T 2 prepared inversion recovery; peripheral arteries Arterial wall thickening is regarded a surrogate marker of atherosclerosis, and wall thickness has been used to predict the risk of future cardiovascular events (1,2). Ultrasound imaging can measure the intima-media thickness (3), while MRI has been utilized for assessment of vessel wall thickness, with the added benefits of plaque characterization and higher spatial resolution (4). Both techniques have been employed in serial imaging studies to measure wall thickness changes in response to drug therapy (5,6).Vessel wall MRI requires suppression of blood signal (''black blood'' [BB]) to delineate the vessel wall from the lumen. BB imaging is commonly performed using double inversion recovery (DIR) preparation (7,8) or spatial saturation of upstream blood (9,10), followed by data acquisition such as fast spin echo (FSE) readout. DIR and spatial saturation blood suppression rely on the inflow of blood with nulled signal into the imaging volume and are therefore a function of volume thickness, blood velocity, and flow pattern. These techniques provide excellent blood suppression for two-dimensional (2D) imaging of arteries with fast blood flow such as the aorta but may be less effective for three-dimensional volumetric imaging and in the presence of recirculating or slow blood flow such as that observed near the carotid bifurcation (11) and in the peripheral arteries. To overcome these challenges, several BB preparation techniques have been recently developed, including motion-sensitizing magnetization preparation (MSPREP) and T 2 -prepared inversion recovery (T2IR). MSPREP employs large velocityencoding gradients to dephase moving blood spins prior to imaging and has been demonstrated to perform well in the heart (12), the aorta (13), and the carotid artery (14). Originally developed to suppress background in peripheral MR angiography (15), T2IR preparation has been proposed as a flexible technique to enhance blood-myocardium c...

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Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single‐center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal‐fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%–22.1%) and mean volumes (119.7–160.4 mm 3 ) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29–6.30]), male sex (OR, 2.27 [95% CI, 1.03–5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03–1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43–0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE‐related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.