Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.

BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).

Segmentation of supragranular and infragranular layers in ultra-high-resolution 7T ex vivo MRI of the human cerebral cortex.

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Building on recent advancements in ultra-high-resolution ex vivo MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers in ex vivo MRI with unprecedented precision. On a dataset consisting of 17 whole-hemisphere ex vivo scans at 120 $\mu $m, we propose a Multi-resolution U-Nets framework that integrates global and local structural information, achieving reliable segmentation maps of the entire hemisphere, with Dice scores over 0.8 for supra- and infragranular layers. This enables surface modeling, atlas construction, anomaly detection in disease states, and cross-modality validation while also paving the way for finer layer segmentation. Our approach offers a powerful tool for comprehensive neuroanatomical investigations and holds promise for advancing our mechanistic understanding of progression of neurodegenerative diseases.

Comparison of prospective and retrospective motion correction in 3D-encoded neuroanatomical MRI.

PURPOSE: To compare prospective motion correction (PMC) and retrospective motion correction (RMC) in Cartesian 3D-encoded MPRAGE scans and to investigate the effects of correction frequency and parallel imaging on the performance of RMC. METHODS: Head motion was estimated using a markerless tracking system and sent to a modified MPRAGE sequence, which can continuously update the imaging FOV to perform PMC. The prospective correction was applied either before each echo train (before-ET) or at every sixth readout within the ET (within-ET). RMC was applied during image reconstruction by adjusting k-space trajectories according to the measured motion. The motion correction frequency was retrospectively increased with RMC or decreased with reverse RMC. Phantom and in vivo experiments were used to compare PMC and RMC, as well as to compare within-ET and before-ET correction frequency during continuous motion. The correction quality was quantitatively evaluated using the structural similarity index measure with a reference image without motion correction and without intentional motion. RESULTS: PMC resulted in superior image quality compared to RMC both visually and quantitatively. Increasing the correction frequency from before-ET to within-ET reduced the motion artifacts in RMC. A hybrid PMC and RMC correction, that is, retrospectively increasing the correction frequency of before-ET PMC to within-ET, also reduced motion artifacts. Inferior performance of RMC compared to PMC was shown with GRAPPA calibration data without intentional motion and without any GRAPPA acceleration. CONCLUSION: Reductions in local Nyquist violations with PMC resulted in superior image quality compared to RMC. Increasing the motion correction frequency to within-ET reduced the motion artifacts in both RMC and PMC.

Automated detection and reacquisition of motion-degraded images in fetal HASTE imaging at 3 T.

PURPOSE: Fetal brain Magnetic Resonance Imaging suffers from unpredictable and unconstrained fetal motion that causes severe image artifacts even with half-Fourier single-shot fast spin echo (HASTE) readouts. This work presents the implementation of a closed-loop pipeline that automatically detects and reacquires HASTE images that were degraded by fetal motion without any human interaction. METHODS: A convolutional neural network that performs automatic image quality assessment (IQA) was run on an external GPU-equipped computer that was connected to the internal network of the MRI scanner. The modified HASTE pulse sequence sent each image to the external computer, where the IQA convolutional neural network evaluated it, and then the IQA score was sent back to the sequence. At the end of the HASTE stack, the IQA scores from all the slices were sorted, and only slices with the lowest scores (corresponding to the slices with worst image quality) were reacquired. RESULTS: The closed-loop HASTE acquisition framework was tested on 10 pregnant mothers, for a total of 73 acquisitions of our modified HASTE sequence. The IQA convolutional neural network, which was successfully employed by our modified sequence in real time, achieved an accuracy of 85.2% and area under the receiver operator characteristic of 0.899. CONCLUSION: The proposed acquisition/reconstruction pipeline was shown to successfully identify and automatically reacquire only the motion degraded fetal brain HASTE slices in the prescribed stack. This minimizes the overall time spent on HASTE acquisitions by avoiding the need to repeat the entire stack if only few slices in the stack are motion-degraded.

Combined acquisition of diffusion and T2*-weighted measurements using simultaneous multi-contrast magnetic resonance imaging.

OBJECT: In this work, we present a technique called simultaneous multi-contrast imaging (SMC) to acquire multiple contrasts within a single measurement. Simultaneous multi-slice imaging (SMS) shortens scan time by allowing the repetition time (TR) to be reduced for a given number of slices. SMC imaging preserves TR, while combining different scan types into a single acquisition. This technique offers new opportunities in clinical protocols where examination time is a critical factor and multiple image contrasts must be acquired. MATERIALS AND METHODS: High-resolution, navigator-corrected, diffusion-weighted imaging was performed simultaneously with T2*-weighted acquisition at 3 T in a phantom and in five healthy subjects using an adapted readout-segmented EPI sequence (rs-EPI). RESULTS: The results demonstrated that simultaneous acquisition of two contrasts (here diffusion-weighted imaging and T2*-weighting) with SMC imaging is feasible with robust separation of contrasts and minimal effect on image quality. DISCUSSION: The simultaneous acquisition of multiple contrasts reduces the overall examination time and there is an inherent registration between contrasts. By using the results of this study to control saturation effects in SMC, the method enables rapid acquisition of distortion-matched and well-registered diffusion-weighted and T2*-weighted imaging, which could support rapid diagnosis and treatment of acute stroke.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

Navigator-based reacquisition and estimation of motion-corrupted data: Application to multi-echo spin echo for carotid wall MRI.

PURPOSE: To assess whether artifacts in multi-slice multi-echo spin echo neck imaging, thought to be caused by brief motion events such as swallowing, can be corrected by reacquiring corrupted central k-space data and estimating the remainder with parallel imaging. METHODS: A single phase-encode line (ky = 0, phase-encode direction anteroposterior) navigator echo was used to identify motion-corrupted data and guide the online reacquisition. If motion corruption was detected in the 7 central k-space lines, they were replaced with reacquired data. Subsequently, GRAPPA reconstruction was trained on the updated central portion of k-space and then used to estimate the remaining motion-corrupted k-space data from surrounding uncorrupted data. Similar compressed sensing-based approaches have been used previously to compensate for respiration in cardiac imaging. The g-factor noise amplification was calculated for the parallel imaging reconstruction of data acquired with a 10-channel neck coil. The method was assessed in scans with 9 volunteers and 12 patients. RESULTS: The g-factor analysis showed that GRAPPA reconstruction of 2 adjacent motion-corrupted lines causes high noise amplification; therefore, the number of 2-line estimations should be limited. In volunteer scans, median ghosting reduction of 24% was achieved with 2 adjacent motion-corrupted lines correction, and image quality was improved in 2 patient scans that had motion corruption close to the center of k-space. CONCLUSION: Motion-corrupted echo-trains can be identified with a navigator echo. Combined reacquisition and parallel imaging estimation reduced motion artifacts in multi-slice MESE when there were brief motion events, especially when motion corruption was close to the center of k-space.

Markerless high-frequency prospective motion correction for neuroanatomical MRI.

PURPOSE: To integrate markerless head motion tracking with prospectively corrected neuroanatomical MRI sequences and to investigate high-frequency motion correction during imaging echo trains. METHODS: A commercial 3D surface tracking system, which estimates head motion by registering point cloud reconstructions of the face, was used to adapt the imaging FOV based on head movement during MPRAGE and T2 SPACE (3D variable flip-angle turbo spin-echo) sequences. The FOV position and orientation were updated every 6 lines of k-space (< 50 ms) to enable "within-echo-train" prospective motion correction (PMC). Comparisons were made with scans using "before-echo-train" PMC, in which the FOV was updated only once per TR, before the start of each echo train (ET). Continuous-motion experiments with phantoms and in vivo were used to compare these high-frequency and low-frequency correction strategies. MPRAGE images were processed with FreeSurfer to compare estimates of brain structure volumes and cortical thickness in scans with different PMC. RESULTS: The median absolute pose differences between markerless tracking and MR image registration were 0.07/0.26/0.15 mm for x/y/z translation and 0.06º/0.02º/0.12° for rotation about x/y/z. The PMC with markerless tracking substantially reduced motion artifacts. The continuous-motion experiments showed that within-ET PMC, which minimizes FOV encoding errors during ETs that last over 1 second, reduces artifacts compared with before-ET PMC. T2 SPACE was found to be more sensitive to motion during ETs than MPRAGE. FreeSurfer morphometry estimates from within-ET PMC MPRAGE images were the most accurate. CONCLUSION: Markerless head tracking can be used for PMC, and high-frequency within-ET PMC can reduce sensitivity to motion during long imaging ETs.

Human Cytomegalovirus Utilizes a Nontraditional Signal Transducer and Activator of Transcription 1 Activation Cascade via Signaling through Epidermal Growth Factor Receptor and Integrins To Efficiently Promote the Motility, Differentiation, and Polarization of Infected Monocytes.

Human cytomegalovirus (HCMV) infects peripheral blood monocytes and triggers biological changes that promote viral dissemination and persistence. We have shown that HCMV induces a proinflammatory state in infected monocytes, resulting in enhanced monocyte motility and transendothelial migration, prolonged monocyte survival, and differentiation toward a long-lived M1-like macrophage phenotype. Our data indicate that HCMV triggers these changes, in the absence of de novo viral gene expression and replication, through engagement and activation of epidermal growth factor receptor (EGFR) and integrins on the surface of monocytes. We previously identified that HCMV induces the upregulation of multiple proinflammatory gene ontologies, with the interferon-associated gene ontology exhibiting the highest percentage of upregulated genes. However, the function of the HCMV-induced interferon (IFN)-stimulated genes (ISGs) in infected monocytes remained unclear. We now show that HCMV induces the enhanced expression and activation of a key ISG transcriptional regulator, signal transducer and activator of transcription (STAT1), via an IFN-independent but EGFR- and integrin-dependent signaling pathway. Furthermore, we identified a biphasic activation of STAT1 that likely promotes two distinct phases of STAT1-mediated transcriptional activity. Moreover, our data show that STAT1 is required for efficient early HCMV-induced enhanced monocyte motility and later for HCMV-induced monocyte-to-macrophage differentiation and for the regulation of macrophage polarization, suggesting that STAT1 may serve as a molecular convergence point linking the biological changes that occur at early and later times postinfection. Taken together, our results suggest that HCMV reroutes the biphasic activation of a traditionally antiviral gene product through an EGFR- and integrin-dependent pathway in order to help promote the proviral activation and polarization of infected monocytes.IMPORTANCE HCMV promotes multiple functional changes in infected monocytes that are required for viral spread and persistence, including their enhanced motility and differentiation/polarization toward a proinflammatory M1 macrophage. We now show that HCMV utilizes the traditionally IFN-associated gene product, STAT1, to promote these changes. Our data suggest that HCMV utilizes EGFR- and integrin-dependent (but IFN-independent) signaling pathways to induce STAT1 activation, which may allow the virus to specifically dictate the biological activity of STAT1 during infection. Our data indicate that HCMV utilizes two phases of STAT1 activation, which we argue molecularly links the biological changes that occur following initial binding to those that continue to occur days to weeks following infection. Furthermore, our findings may highlight a unique mechanism for how HCMV avoids the antiviral response during infection by hijacking the function of a critical component of the IFN response pathway.

First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

High-resolution diffusion MRI at 7T using a three-dimensional multi-slab acquisition.

High-resolution diffusion MRI can provide the ability to resolve small brain structures, enabling investigations of detailed white matter architecture. A major challenge for in vivo high-resolution diffusion MRI is the low signal-to-noise ratio. In this work, we combine two highly compatible methods, ultra-high field and three-dimensional multi-slab acquisition to improve the SNR of high-resolution diffusion MRI. As each kz plane is encoded using a single-shot echo planar readout, scan speeds of the proposed technique are similar to the commonly used two-dimensional diffusion MRI. In-plane parallel acceleration is applied to reduce image distortions. To reduce the sensitivity of auto-calibration signal data to subject motion and respiration, several new adaptions of the fast low angle excitation echo-planar technique (FLEET) that are suitable for 3D multi-slab echo planar imaging are proposed and evaluated. A modified reconstruction scheme is proposed for auto-calibration with the most robust method, Slice-FLEET acquisition, to make it compatible with navigator correction of motion induced phase errors. Slab boundary artefacts are corrected using the nonlinear slab profile encoding method recently proposed by our group. In vivo results demonstrate that using 7T and three-dimensional multi-slab acquisition with improved auto-calibration signal acquisition and nonlinear slab boundary artefacts correction, high-quality diffusion MRI data with ~1mm isotropic resolution can be achieved.

Reducing slab boundary artifacts in three-dimensional multislab diffusion MRI using nonlinear inversion for slab profile encoding (NPEN).

PURPOSE: To propose a method to reduce the slab boundary artifacts in three-dimensional multislab diffusion MRI. METHODS: Bloch simulation is used to investigate the effects of multiple factors on slab boundary artifacts, including characterization of residual errors on diffusion quantification. A nonlinear inversion method is proposed to simultaneously estimate the slab profile and the underlying (corrected) image. RESULTS: Correction results of numerical phantom and in vivo data demonstrate that the method can effectively remove slab boundary artifacts for diffusion data. Notably, the nonlinear inversion is also successful at short TR, a regimen where previously proposed methods (slab profile encoding and weighted average) retain residual artifacts in both diffusion-weighted images and diffusion metrics (mean diffusion coefficient and fractional anisotropy). CONCLUSION: The nonlinear inversion for removing slab boundary artifacts provides improvements over existing methods, particularly at the short TRs required to maximize SNR efficiency. Magn Reson Med 76:1183-1195, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Prospective motion correction and selective reacquisition using volumetric navigators for vessel-encoded arterial spin labeling dynamic angiography.

PURPOSE: The aim of this study was to improve robustness to motion in a vessel-encoded angiography sequence used for patient scans. The sequence is particularly sensitive to motion between imaging segments, which causes ghosting and blurring that propagates to the final angiogram. METHODS: Volumetric echo planar imaging (EPI) navigators acquired in 275 ms were inserted after the imaging readout in a vessel-encoded pseudo-continuous arterial spin labeling (VEPCASL) sequence. The effects of movement between segments on the images were tested with phantom experiments. Deliberate motion experiments with healthy volunteers were performed to compare prospective motion correction (PMC) with reacquisition versus no correction. RESULTS: In scans without motion, the addition of the EPI navigator to the sequence did not affect the quality of the angiograms in comparison with the original sequence. PMC and reacquisition improved the visibility of vessels in the angiograms compared with the scans without correction. The reacquisition strategy was shown to be important for complete correction of imaging artifacts. CONCLUSION: We have demonstrated an effective method to correct motion in vessel-encoded angiography. For reacquisition of 15 segments, the technique requires approximately 30 s of additional scanning (∼25%). Magn Reson Med 76:1420-1430, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Scan time reduction for readout-segmented EPI using simultaneous multislice acceleration: Diffusion-weighted imaging at 3 and 7 Tesla.

PURPOSE: Readout-segmented echo-planar imaging (rs-EPI) can provide high quality diffusion data because it is less prone to distortion and blurring artifacts than single-shot echo-planar imaging (ss-EPI), particularly at higher resolution and higher field. Readout segmentation allows shorter echo-spacing and echo train duration, resulting in reduced image distortion and blurring, respectively, in the phase-encoding direction. However, these benefits come at the expense of longer scan times because the segments are acquired in multiple repetitions times (TRs). This study shortened rs-EPI scan times by reducing the TR duration with simultaneous multislice acceleration. METHODS: The blipped-CAIPI method for slice acceleration with reduced g-factor SNR loss was incorporated into the diffusion-weighted rs-EPI sequence. The rs- and ss-EPI sequences were compared at a range of resolutions at both 3 and 7 Tesla in terms of image fidelity and diffusion postprocessing results. RESULTS: Slice-accelerated clinically useful trace-weighted images and tractography results are presented. Tractography analysis showed that the reduced artifacts in rs-EPI allowed better discrimination of tracts than ss-EPI. CONCLUSION: Slice acceleration reduces rs-EPI scan times providing a practical alternative to diffusion-weighted ss-EPI with reduced distortion and high resolution. Magn Reson Med 74:136-149, 2015. © 2014 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

Accelerated human cardiac diffusion tensor imaging using simultaneous multislice imaging.

PURPOSE: To demonstrate the feasibility of accelerating measurements of cardiac fiber structure using simultaneous multislice (SMS) imaging. METHODS: SMS excitation with a blipped controlled aliasing (CAIPI) readout was incorporated into a diffusion-encoded stimulated echo pulse sequence to obtain diffusion measurements in three separate slices of the heart (8-mm thickness, 12-mm gap). A novel image entropy-based method for removing image ghosts in blipped CAIPI acquisitions is also introduced that enables SMS imaging of closely spaced slices in the heart. RESULTS: The average retained signal-to-noise ratio (SNR) using this acquisition scheme is 70% ± 5%, higher than the standard 1/3 = 57% SNR penalty with three-fold acceleration. No significant difference was observed in the apparent diffusion coefficient and helix angle diffusion parameters between a time-equivalent conventional single-slice scan and the three-fold accelerated SMS acquisition. A 10% mean bias was observed in fractional anisotropy between single-slice and SMS acquisitions. CONCLUSION: The new sequence was used to obtain high-quality diffusion measurements in three closely spaced cardiac slices in a clinically feasible nine breath-hold examination. The accelerated multiband sequence is anticipated to improve quantitative measurements of cardiac microstructure by reducing the number of breath-holds required for the scan, making it practical to incorporate diffusion tensor measurements within a comprehensive clinical examination.

3D multi-slab diffusion-weighted readout-segmented EPI with real-time cardiac-reordered K-space acquisition.

PURPOSE: The aim of this study was to develop, implement, and demonstrate a three-dimensional (3D) extension of the readout-segmented echo-planar imaging (rs-EPI) sequence for diffusion imaging. THEORY AND METHODS: Potential k-space acquisition schemes were assessed by simulating their associated spatial point spread functions. Motion-induced phase artifacts were also simulated to test navigator corrections and a real-time reordering of the k-space acquisition relative to the cardiac cycle. The cardiac reordering strategy preferentially chooses readout segments closer to the center of 3D k-space during diastole. Motion-induced phase artifacts were quantified by calculating the voxel-wise temporal variation in a set of repeated diffusion-weighted acquisitions. Based on the results of these simulations, a 2D navigated multi-slab rs-EPI sequence with real-time cardiac reordering was implemented. The multi-slab implementation enables signal-to-noise ratio-optimal repetition times of 1-2 s. RESULTS: Cardiac reordering was validated in simulations and in vivo using the multi-slab rs-EPI sequence. In comparisons with standard k-space acquisitions, cardiac reordering was shown to reduce the variability due to motion-induced phase artifacts by 30-50%. High-resolution diffusion tensor imaging data acquired with the cardiac-reordered multi-slab rs-EPI sequence are presented. CONCLUSION: A 3D multi-slab rs-EPI sequence with cardiac reordering has been demonstrated in vivo and is shown to provide high-quality 3D diffusion-weighted data sets.

Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs.

Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes.

Diagnosis of Barth syndrome using a novel LC-MS/MS method for leukocyte cardiolipin analysis.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and 3-methylglutaconic aciduria. It is caused by mutations in the TAZ gene which codes for tafazzin, a protein with acyl transferase activity involved in synthesis of cardiolipin. Monolysocardiolipin (MLCL) is an intermediate in this process. Diagnosis of BTHS is difficult, as clinical and biochemical features are variable and numerous TAZ mutations have been described. These factors, together with lack of a straightforward diagnostic test are thought to have contributed to under-diagnosis of the condition. A novel method for cardiolipin analysis by reversed-phase ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is reported which is less complicated and faster than previously described methods and uses a readily available sample type. The equipment, reagents and expertise required are found in most clinical laboratories performing metabolic investigations. Leukocytes were prepared from whole blood, phospholipids extracted and tetralinoleyl cardiolipin (CL4) and MLCL analysed by UPLC-MS/MS. Reference values were derived from analysis of 76 control and 23 BTHS samples as follows: CL4 in controls >132 (95 % CI 100-169), BTHS <30.2 (21.3-40.4) pmol/mg protein; MLCL/CL4 ratio in controls <0.006 (0.004-0.009) and >2.52 (1.51-4.22) in BTHS patients. We describe an improved method for CL4 and MLCL/CL4 analysis which can be incorporated into the routine work of a clinical biochemistry laboratory. It shows 100 % sensitivity and specificity for BTHS, making it a suitable diagnostic test.

MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs.

Piwi-interacting RNAs (piRNAs) comprise a broad class of small noncoding RNAs that function as an endogenous defense system against transposable elements. Here we show that the putative DExD-box helicase MOV10-like-1 (MOV10L1) is essential for silencing retrotransposons in the mouse male germline. Mov10l1 is specifically expressed in germ cells with increasing expression from gonocytes/type A spermatogonia to pachytene spermatocytes. Primary spermatocytes of Mov10l1(-/-) mice show activation of LTR and LINE-1 retrotransposons, followed by cell death, causing male infertility and a complete block of spermatogenesis at early prophase of meiosis I. Despite the early expression of Mov10l1, germline stem cell maintenance appears unaffected in Mov10l1(-/-) mice. MOV10L1 interacts with the Piwi proteins MILI and MIWI. MOV10L1 also interacts with heat shock 70-kDa protein 2 (HSPA2), a testis-enriched chaperone expressed in pachytene spermatocytes and also essential for male fertility. These studies reveal a crucial role of MOV10L1 in male fertility and piRNA-directed retrotransposon silencing in male germ cells and suggest that MOV10L1 functions as a key component of a safeguard mechanism for the genetic information in male germ cells of mammals.

Can we predict motion artifacts in clinical MRI before the scan completes?

Subject motion can cause artifacts in clinical MRI, frequently necessitating repeat scans. We propose to alleviate this inefficiency by predicting artifact scores from partial multi-shot multi-slice acquisitions, which may guide the operator in aborting corrupted scans early.