This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

Intraepithelial lymphocytes (IELs) of the small intestine are intimately associated with the epithelial cells. Yet, the factors controlling their migration and interaction dynamics are poorly understood. We demonstrate that GPR55, a receptor that mediates migration inhibition in response to lysophosphatidylinositol (LPI), negatively regulates T cell receptor γδ (TCRγδ) IEL accumulation in the small intestine. Intravital imaging studies show that GPR55-deficient IELs migrate faster and interact more extensively with epithelial cells. GPR55 also negatively regulates T cell homing to the small intestine and γδT cell egress from Peyer's patches. GPR55 deficiency or short-term antagonist treatment protects from nonsteroidal anti-inflammatory drug-induced increases in intestinal permeability. These findings identify a migration-inhibitory receptor that restrains IEL-epithelial cell cross-talk and show that antagonism of this receptor can protect from intestinal barrier dysfunction.

Purpose

A novel application of two-dimensional (2D) spatially selective radiofrequency (2DRF) excitation pulses in hyperpolarized 13C imaging is proposed for monitoring the bolus injection with highly efficient sampling of the initially polarized substrate, thus leaving more polarization available for detection of the subsequently generated metabolic products.

Methods

A 2DRF pulse was designed with a spiral trajectory and conventional clinical gradient performance. To demonstrate the ability of our 2DRF bolus tracking pulse sequence, hyperpolarized [1-(13)ruvate in vivo imaging experiments were performed in normal rats, with a comparison to 1DRF excitation pulses.

Results

Our designed 2DRF pulse was able to rapidly and efficiently monitor the injected bolus dynamics in vivo, with an 8-fold enhanced time resolution in comparison with 1DRF in our experimental settings. When applied at the pyruvate frequency for bolus tracking, our 2DRF pulse demonstrated reduced saturation of the hyperpolarization for the substrate and metabolic products compared to a 1DRF pulse, while being immune to ±0.5 ppm magnetic field inhomogeneity at 3T.

Conclusion

2DRF pulses in hyperpolarized 13C imaging can be used to efficiently monitor the bolus injection with reduced hyperpolarization saturation compared to 1DRF pulses. The parameters of our design are based on clinical scanner limits, which allows for rapid translation to human studies.

Sheep red blood cells (SRBCs) have long been used as a model antigen for eliciting systemic immune responses, yet the basis for their adjuvant activity has been unknown. Here, we show that SRBCs failed to engage the inhibitory mouse SIRPα receptor on splenic CD4(+) dendritic cells (DCs), and this failure led to DC activation. Removal of the SIRPα ligand, CD47, from self-RBCs was sufficient to convert them into an adjuvant for adaptive immune responses. DC capture of Cd47(-/-) RBCs and DC activation occurred within minutes in a Src-family-kinase- and CD18-integrin-dependent manner. These findings provide an explanation for the adjuvant mechanism of SRBCs and reveal that splenic DCs survey blood cells for missing self-CD47, a process that might contribute to detecting and mounting immune responses against pathogen-infected RBCs.

¹³C-bicarbonate is a crucial measure of pyruvate oxidation and TCA cycle flux, but is challenging to measure due to its relatively low concentration and thus will greatly benefit from improved signal-to-noise ratio (SNR). To address this, we developed and investigated the feasibility of a 3D stack-of-spirals metabolite-specific balanced steady-state free precession (MS-bSSFP) sequence for improving the SNR and spatial resolution of dynamic ¹³C-bicarbonate imaging in hyperpolarized [1-¹³C]pyruvate studies. The bicarbonate MS-bSSFP sequence was evaluated by simulations, phantoms studies, preclinical studies on five rats, brain studies on two healthy volunteers and renal study on one renal cell carcinoma patient. The simulations and phantom results showed that the bicarbonate-specific pulse had minimal perturbation of other metabolites (<1%). In the animal studies, the MS-bSSFP sequence provided an approximately 2.6-3 × improvement in ¹³C-bicarbonate SNR compared to a metabolite-specific gradient echo (MS-GRE) sequence without altering the bicarbonate or pyruvate kinetics, and the shorter spiral readout in the MS-bSSFP approach reduced blurring. Using the SNR ratio between MS-bSSFP and MS-GRE, the T₂ values of bicarbonate and lactate in the rat kidneys were estimated as 0.5 s and 1.1 s, respectively. The in-vivo feasibility of bicarbonate MS-bSSFP sequence was demonstrated in two human brain studies and one renal study. These studies demonstrate the potential of the sequence for in-vivo applications, laying the foundation for future studies to observe this relatively low concentration metabolite with high-quality images and improve measurements of pyruvate oxidation.

B cells within germinal centers (GCs) enter cycles of antibody affinity maturation or exit the GC as memory cells or plasma cells. Here, we examined the contribution of interleukin (IL)-4 on B cell fate decisions in the GC. Single-cell RNA-sequencing identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature. These cells could differentiate into pre-memory cells. B cell-specific deletion of IL4Ra or STAT6 favored the pre-memory cell trajectory, and provision of exogenous IL-4 in a wild-type context reduced pre-memory cell frequencies. IL-4 acted during antigen-specific interactions but also influenced bystander cells. Deletion of IL4Ra from follicular dendritic cells (FDCs) increased the availability of IL-4 in the GC, impaired the selection of affinity-matured B cells, and reduced memory cell generation. We propose that GC FDCs establish a niche that limits bystander IL-4 activity, focusing IL-4 action on B cells undergoing selection and enhancing memory cell differentiation.

Purpose

Hyperpolarized ¹³ C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types.

Methods

Baseline gadoxetate uptake kinetics were measured using T₁ -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-¹³ C]pyruvate, [1-¹³ C]lactate, and [1-¹³ C]alanine. Four healthy rats were imaged with hyperpolarized [1-¹³ C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney.

Results

Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P < 0.05) following gadoxetate administration. In kidneys, these ratios did not change significantly. Relaxivity of gadoxetate for [1-¹³ C]alanine was 12.6 times higher than relaxivity of gadoxetate for [1-¹³ C]pyruvate, explaining the greater selective relaxation effect on alanine.

Conclusions

The liver-specific gadolinium contrast-agent gadoxetate can selectively suppress normal hepatocyte contributions to hyperpolarized ¹³ C MRI signals. Magn Reson Med 77:2356-2363, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

Endoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance.

Methods

Two variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.2 MHz planar; or 8 × 10 × 20 mm radius of curvature 3.3 MHz curvilinear geometries) at the distal end of a meter long flexible catheter assembly, were designed and fabricated. Transducers and circulatory water flow for acoustic coupling and luminal cooling were contained by a low-profile polyester balloon covering the transducer assembly fixture. Each applicator incorporated miniature spiral MR coils and mechanical features (guiding tips and hinges) to facilitate tracking and insertion through the GI tract under MRI guidance. Acoustic characterization of each device was performed using radiation force balance and hydrophone measurements. Device delivery into the upper GI tract, adjacent to the pancreas, and heating characteristics for treatment of pancreatic tissue were evaluated in MR-guided ex vivo and in vivo porcine experiments. MR guidance was utilized for anatomical target identification, tracking/positioning of the applicator, and MR temperature imaging (MRTI) for PRF-based multislice thermometry, implemented in the real-time RTHawk software environment.

Results

Force balance and hydrophone measurements indicated efficiencies of 48.8% and 47.8% and -3 dB intensity beam-widths of 3.2 and 1.2 mm for the planar and curvilinear transducers, respectively. Ex vivo studies on whole-porcine carcasses revealed capabilities of producing ablative temperature rise (ΔT > 15 °C) contours in pancreatic tissue 4-40 mm long and 4-28 mm wide for the planar transducer applicator (1-13 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Curvilinear transducers produced more selective heating, with a narrower ΔT > 15 °C contour length and width of up to 1-24 mm and 2-7 mm, respectively (1-7 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Active tracking of the miniature spiral coils was achieved using a Hadamard encoding tracking sequence, enabling real-time determination of each coil's coordinates and automated prescription of imaging planes for thermometry. In vivo MRTI-guided heating trials in three pigs demonstrated capability of ∼20 °C temperature elevation in pancreatic tissue at 2 cm depths from the applicator, with 5-7 W/cm(2) applied intensity and 6-16 min sonication duration. Dimensions of thermal lesions in the pancreas ranged from 12 to 28 mm, 3 to 10 mm, and 5 to 10 mm in length, width, and depth, respectively, as verified through histological analysis of tissue sections. Multiple-baseline reconstruction and respiratory-gated acquisition were demonstrated to be effective strategies in suppressing motion artifacts for clear evolution of temperature profiles during MRTI in the in vivo studies.

Conclusions

This study demonstrates the technical feasibility of generating volumetric ablation in pancreatic tissue using endoluminal ultrasound applicators positioned in the stomach lumen. MR guidance facilitates target identification, device tracking/positioning, and treatment monitoring through real-time multislice PRF-based thermometry.