A double-strand break can trigger immunoglobulin gene conversion

All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system-gene conversion, somatic hypermutation and class switch recombination-require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease. Here, we show that a double-strand break (DSB) in CDR1 is sufficient to trigger Ig gene conversion in the absence of AID. The pattern and pseudogene usage of DSB-induced gene conversion were comparable to those of AID-induced gene conversion; surprisingly, sometimes a single DSB induced multiple gene conversion events. These constitute direct evidence that a DSB in the V region can be an intermediate for gene conversion. The fate of the DNA lesion downstream of a DSB had more flexibility than that of AID, suggesting two alternative models: (i) DSBs during the physiological gene conversion are in the minority compared to single-strand breaks (SSBs), which are frequently generated following DNA deamination, or (ii) the physiological gene conversion is mediated by a tightly regulated DSB that is locally protected from non-homologous end joining (NHEJ) or other non-homologous DNA recombination machineries

DTI and MR Volumetry of Hippocampus-PC/PCC Circuit: In Search of Early Micro- and Macrostructural Signs of Alzheimers's Disease

Hippocampal damage, by DTI or MR volumetry, and PET hypoperfusion of precuneus/posterior cingulate cortex (PC/PCC) were proposed as biomarkers of conversion from preclinical (MCI) to clinical stage of Alzheimer's disease (AD). This study evaluated structural damage, by DTI and MR volumetry, of hippocampi and tracts connecting hippocampus to PC/PCC (hipp-PC/PCC) in 10 AD, 10 MCI, and 18 healthy controls (CTRL). Normalized volumes, mean diffusivity (MD), and fractional anisotropy (FA) were obtained for grey matter (GM), white matter (WM), hippocampi, PC/PCC, and hipp-PC/PCC tracts. In hippocampi and hipp-PC/PCC tracts, decreased volumes and increased MD were found in AD versus CTRL (P < .001). The same results with lower significance (P < .05) were found in MCI versus CTRL. Verbal memory correlated (P < .05) in AD with left hippocampal and hipp-PC/PCC tract MD, and in MCI with FA of total WM. Both DTI and MR volumetry of hippocampi and hipp-PC/PCC tracts detect early signs of AD in MCI patients

Variable echo time imaging for detecting the short T2* components of the sciatic nerve: a validation study

OBJECTIVE: The aim of this study was to develop and validate an MRI protocol based on a variable echo time (vTE) sensitive to the short T2* components of the sciatic nerve. MATERIALS AND METHODS: 15 healthy subjects (M/F: 9/6; age: 21-62) were scanned at 3T targeting the sciatic nerve at the thigh bilaterally, using a dual echo variable echo time (vTE) sequence (based on a spoiled gradient echo acquisition) with echo times of 0.98/5.37 ms. Apparent T2* (aT2*) values of the sciatic nerves were calculated with a mono-exponential fit and used for data comparison. RESULTS: There were no significant differences in aT2* related to side, sex, age, and BMI, even though small differences for side were reported. Good-to-excellent repeatability and reproducibility were found for geometry of ROIs (Dice indices: intra-rater 0.68-0.7; inter-rater 0.70-0.72) and the related aT2* measures (intra-inter reader ICC 0.95-0.97; 0.66-0.85) from two different operators. Side-related signal-to-noise-ratio non-significant differences were reported, while contrast-to-noise-ratio measures were excellent both for side and echo. DISCUSSION: Our study introduces a novel MR sequence sensitive to the short T2* components of the sciatic nerve and may be used for the study of peripheral nerve disorders

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort

Does higher gadolinium concentration play a role in the morphologic assessment of brain tumors? Results of a multicenter intraindividual crossover comparison of gadobutrol versus gadobenate dimeglumine (the MERIT Study).

BACKGROUND AND PURPOSE: Gadobenate dimeglumine has proved advantageous compared with other gadolinium-based contrast agents for contrast-enhanced brain MR imaging. Gadobutrol is a more highly concentrated agent (1.0 mol/L). This study intraindividually compared 0.1-mmol/kg doses of these agents for qualitative and quantitative evaluation of brain tumors. MATERIALS AND METHODS: Adult patients with suspected or known brain tumors underwent 2 identical MR imaging examinations at 1.5T, 1 with gadobenate dimeglumine and the other with gadobutrol, both at a dose of 0.1-mmol/kg body weight. The agents were injected in randomized order separated by 3–14 days. Imaging sequences and acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images qualitatively for diagnostic information (lesion extent, delineation, morphology, enhancement, global preference) and quantitatively for CNR and LBR. RESULTS: One hundred fourteen of 123 enrolled patients successfully underwent both examinations. Final diagnoses were intra-axial tumors, metastases, extra-axial tumors, "other" tumors, and "nontumor" (49, 46, 8, 7, and 4 subjects, respectively). Readers 1, 2, and 3 demonstrated preference for gadobenate dimeglumine in 46 (40.7%), 54 (47.4%), and 49 (43.0%) patients, respectively, compared with 6, 7, and 7 patients for gadobutrol ( P < .0001, all readers). Highly significant ( P < .0001, all readers) preference for gadobenate dimeglumine was demonstrated for all other qualitative end points. Inter-reader agreement was good for all evaluations (κ = 0.414–0.629). Significantly superior CNR and LBR were determined for gadobenate dimeglumine ( P < .019, all readers). CONCLUSIONS: Significantly greater morphologic information and lesion enhancement are achieved on brain MR imaging with 0.1-mmol/kg gadobenate dimeglumine compared with gadobutrol at an equivalent dose. CNR : contrast-to-noise ratio GBCA : gadolinium-based contrast agent GRE : gradient-recalled echo LBR : lesion-to-background ratio NSF : nephrogenic systemic fibrosis SE : spin-echo SI : signal intensit

Entanglement Dynamics after a Quench in Ising Field Theory: A Branch Point Twist Field Approach

We extend the branch point twist field approach for the calculation of entanglement entropies to time-dependent problems in 1+1-dimensional massive quantum field theories. We focus on the simplest example: a mass quench in the Ising field theory from initial mass m0 to final mass m. The main analytical results are obtained from a perturbative expansion of the twist field one-point function in the post-quench quasi-particle basis. The expected linear growth of the Rényi entropies at large times mt ≫ 1 emerges from a perturbative calculation at second order. We also show that the Rényi and von Neumann entropies, in infinite volume, contain subleading oscillatory contributions of frequency 2m and amplitude proportional to (mt)−3/2. The oscillatory terms are correctly predicted by an alternative perturbation series, in the pre-quench quasi-particle basis, which we also discuss. A comparison to lattice numerical calculations carried out on an Ising chain in the scaling limit shows very good agreement with the quantum field theory predictions. We also find evidence of clustering of twist field correlators which implies that the entanglement entropies are proportional to the number of subsystem boundary points

From the sinh-Gordon field theory to the one-dimensional Bose gas: exact local correlations and full counting statistics

We derive exact formulas for the expectation value of local observables in a one-dimensional gas of bosons with point-wise repulsive interactions (Lieb-Liniger model). Starting from a recently conjectured expression for the expectation value of vertex operators in the sinh-Gordon field theory, we derive explicit analytic expressions for the one-point K-body correlation functions \u27e8(\u3a8\u2020)K(\u3a8)K\u27e9 in the Lieb-Liniger gas, for arbitrary integer K. These are valid for all excited states in the thermodynamic limit, including thermal states, generalized Gibbs ensembles and non-equilibrium steady states arising in transport settings. Our formulas display several physically interesting applications: most prominently, they allow us to compute the full counting statistics for the particle-number fluctuations in a short interval. Furthermore, combining our findings with the recently introduced generalized hydrodynamics, we are able to study multi-point correlation functions at the Eulerian scale in non-homogeneous settings. Our results complement previous studies in the literature and provide a full solution to the problem of computing one-point functions in the Lieb Liniger model

From the quantum transfer matrix to the quench action: the Loschmidt echo in XXZ Heisenberg spin chains

We consider the computation of the Loschmidt echo after quantum quenches in the interacting XXZ Heisenberg spin chain both for real and imaginary times. We study two-site product initial states, focusing in particular on the N\ue9el and tilted N\ue9el states. We apply the Quantum Transfer Matrix (QTM) approach to derive generalized TBA equations, which follow from the fusion hierarchy of the appropriate QTM's. Our formulas are valid for arbitrary imaginary time and for real times at least up to a time t0, after which the integral equations have to be modified. In some regimes, t0 is seen to be either very large or infinite, allowing to explore in detail the post-quench dynamics of the system. As an important part of our work, we show that for the N\ue9el state our imaginary time results can be recovered by means of the quench action approach, unveiling a direct connection with the quantum transfer matrix formalism. In particular, we show that in the zero-time limit, the study of our TBA equations allows for a simple alternative derivation of the recently obtained Bethe ansatz distribution functions for the N\ue9el, tilted N\ue9el and tilted ferromagnet states