Characterization of integrated Marek's disease virus genomes supports a model of integration by homology-directed recombination and telomere-loop-driven excision.

IMPORTANCE: Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV is only partially controlled by available vaccines, and the virus retains the ability to replicate and spread between vaccinated birds. Following an initial infection, MDV enters a latent state and integrates into host telomeres and this may be a prerequisite for malignant transformation, which is usually fatal. To understand the mechanism that underlies the dynamic relationship between integrated-latent and reactivated MDV, we have characterized integrated MDV (iMDV) genomes and their associated telomeres. This revealed a single orientation among iMDV genomes and the loss of some terminal sequences that is consistent with integration by homology-directed recombination and excision via a telomere-loop-mediated process.

Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals.

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether, we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

Chromosomally Integrated Human Herpesvirus 6: Models of Viral Genome Release from the Telomere and Impacts on Human Health.

Human herpesvirus 6A and 6B, alongside some other herpesviruses, have the striking capacity to integrate into telomeres, the terminal repeated regions of chromosomes. The chromosomally integrated forms, ciHHV-6A and ciHHV-6B, are proposed to be a state of latency and it has been shown that they can both be inherited if integration occurs in the germ line. The first step in full viral reactivation must be the release of the integrated viral genome from the telomere and here we propose various models of this release involving transcription of the viral genome, replication fork collapse, and t-circle mediated release. In this review, we also discuss the relationship between ciHHV-6 and the telomere carrying the insertion, particularly how the presence and subsequent partial or complete release of the ciHHV-6 genome may affect telomere dynamics and the risk of disease.

Inflection Points in Magnetic Resonance Imaging Technology-35 Years of Collaborative Research and Development.

The technology for clinical magnetic resonance imaging (MRI) has advanced with remarkable speed and in such a manner reflecting the influence of 3 forces-collaboration between disciplines, collaboration between academia and industry, and the enabling of software applications by hardware. The forces are evident in the key developments from the past and emerging trends for the future highlighted in this review article. These developments are associated with MRI system attributes, such as wider, shorter, and stronger magnets; specialty magnets and hybrid devices; k space; and the notion that magnetic field gradients perform a Fourier transform on the spatial distribution of magnetization, phased-array coils and parallel imaging, the user interface, the wide range of contrast possible, and applications that exploit motion-induced phase shifts. An attempt is made to show connections between these developments and how the 3 forces mentioned previously will continue to shape the technology used so productively in clinical MRI.

New onset heart failure in a 29-year-old: A case report of isolated left ventricular noncompaction.

A previously healthy 29-year-old patient presented with new onset congestive heart failure. Based on findings on transthoracic echocardiogram (TTE) and cardiac magnetic resonance imaging (MRI) at an outside center, the patient was diagnosed as having a dilated cardiomyopathy with structural abnormalities in the ventricular septum and left ventricular (LV) apex suspicious for myocardial tumor. After referral to our center for further management, repeat TTE revealed findings characteristic of left ventricular non-compaction (LVNC) with severely depressed overall LV systolic function. Review of the outside cardiac MRI supported the diagnosis of LVNC. Final management consisted of traditional medical therapy for congestive heart failure, an implantable cardiac defibrillator (ICD), warfarin anticoagulation for the prevention of thromboembolism and referral for cardiac transplant.

High-order multiband encoding in the heart.

Spatial encoding with multiband selective excitation (e.g., Hadamard encoding) has been restricted to a small number of slices because the RF pulse becomes unacceptably long when more than about eight slices are encoded. In this work, techniques to shorten multiband RF pulses, and thus allow larger numbers of slices, are investigated. A method for applying the techniques while retaining the capability of adaptive slice thickness is outlined. A tradeoff between slice thickness and pulse duration is shown. Simulations and experiments with the shortened pulses confirmed that motion-induced excitation profile blurring and phase accrual were reduced. The connection between gradient hardware limitations, slice thickness, and flow sensitivity is shown. Excitation profiles for encoding 32 contiguous slices of 1-mm thickness were measured experimentally, and the artifact resulting from errors in timing of RF pulse relative to gradient was investigated. A multiband technique for imaging 32 contiguous 2-mm slices, with adaptive slice thickness, was developed and demonstrated for coronary artery imaging in healthy subjects. With the ability to image high numbers of contiguous slices, using relatively short (1-2 ms) RF pulses, multiband encoding has been advanced further toward practical application.

Pulse-wave velocity measured in one heartbeat using MR tagging.

A noninvasive method for measuring the aortic pulse-wave velocity (PWV) in a single heartbeat is introduced. The method sinusoidally tags a column of blood within the vessel, and rapidly acquires a series of 1D projections of the tags as they move (in practice, 64 projections at 4-ms intervals). From these projections, the relative motion of blood at different positions along the vessel is measured. The PWV is obtained by fitting a mathematical model of blood flow to the tag trajectories. Tests of this method in a pulsatile flow phantom are presented using latex and polyurethane tubes. The PWV measured in these tubes was (mean +/- standard deviation) 4.4 +/- 0.5 m/s and 2.3 +/- 0.2 m/s, respectively. The distensibility of each tube was calculated from the PWV (latex = (7 +/- 2) 10(-3) mm Hg(-1), poly. = (25 +/- 4) 10(-3)mmHg(-1)) and found to agree within error with distensibility measurements based on the change of tube area with pressure (latex = (6.3 +/- 0.3) 10(-3)mmHg(-1), poly. = (27 +/- 1) 10(-3) mmHg(-1)). To test its feasibility, the PWV measurement was applied to four normal volunteers. The measured PWV values were 3.9 +/- 0.8 m/s, 3.6 +/- 0.9 m/s, 3.9 +/- 0.5 m/s, and 5.3 +/- 0.8 m/s. By acquiring an independent PWV measurement each heartbeat, errors introduced by arrhythmia and trigger variability appear to be avoided with this method.