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Quality control (QC) is a fundamental component of any study. Diffusion MRI has unique challenges that make manual QC particularly difficult, including a greater number of artefacts than other MR modalities and a greater volume of data. The gold standard is manual inspection of the data, but this process is time-consuming and subjective. Recently supervised learning approaches based on convolutional neural networks have been shown to be competitive with manual inspection. A drawback of these approaches is they still require a manually labelled dataset for training, which is itself time-consuming to produce and still introduces an element of subjectivity. In this work we demonstrate the need for manual labelling can be greatly reduced by training on simulated data, and using a small amount of labelled data for a final calibration step. We demonstrate its potential for the detection of severe movement artefacts, and compare performance to a classifier trained on manually-labelled real data. [ABSTRACT FROM AUTHOR]

Because of their low bandwidth in the phase-encode (PE) direction, the susceptibility-induced off-resonance field causes distortions in echo planar imaging (EPI) images. It is therefore crucial to correct for susceptibility-induced distortions when performing diffusion studies using EPI. The susceptibility-induced field is caused by the object (head) disrupting the field and it is typically assumed that it remains constant within a framework defined by the object, ( i.e. it follows the object as it moves in the scanner). However, this is only approximately true. When a non-spherical object rotates around an axis other than that parallel with the magnetic flux (the z -axis) it changes the way it disrupts the field, leading to different distortions. Hence, if using a single field to correct for distortions there will be residual distortions in the volumes where the object orientation is substantially different to that when the field was measured. In this paper we present a post-processing method for estimating the field as it changes with motion during the course of an experiment. It only requires a single measured field and knowledge of the orientation of the subject when that field was acquired. The volume-to-volume changes of the field as a consequence of subject movement are estimated directly from the diffusion data without the need for any additional or special acquisitions. It uses a generative model that predicts how each volume would look predicated on field change and inverts that model to yield an estimate of the field changes. It has been validated on both simulations and experimental data. The results show that we are able to track the field with high accuracy and that we are able to correct the data for the adverse effects of the changing field. [ABSTRACT FROM AUTHOR]

Most motion correction methods work by aligning a set of volumes together, or to a volume that represents a reference location. These are based on an implicit assumption that the subject remains motionless during the several seconds it takes to acquire all slices in a volume, and that any movement occurs in the brief moment between acquiring the last slice of one volume and the first slice of the next. This is clearly an approximation that can be more or less good depending on how long it takes to acquire one volume and in how rapidly the subject moves. In this paper we present a method that increases the temporal resolution of the motion correction by modelling movement as a piecewise continous function over time. This intra-volume movement correction is implemented within a previously presented framework that simultaneously estimates distortions, movement and movement-induced signal dropout. We validate the method on highly realistic simulated data containing all of these effects. It is demonstrated that we can estimate the true movement with high accuracy, and that scalar parameters derived from the data, such as fractional anisotropy, are estimated with greater fidelity when data has been corrected for intra-volume movement. Importantly, we also show that the difference in fidelity between data affected by different amounts of movement is much reduced when taking intra-volume movement into account. Additional validation was performed on data from a healthy volunteer scanned when lying still and when performing deliberate movements. We show an increased correspondence between the “still” and the “movement” data when the latter is corrected for intra-volume movement. Finally we demonstrate a big reduction in the telltale signs of intra-volume movement in data acquired on elderly subjects. [ABSTRACT FROM AUTHOR]

Despite its great potential in studying brain anatomy and structure, diffusion magnetic resonance imaging (dMRI) is marred by artefacts more than any other commonly used MRI technique. In this paper we present a non-parametric framework for detecting and correcting dMRI outliers (signal loss) caused by subject motion. Signal loss (dropout) affecting a whole slice, or a large connected region of a slice, is frequently observed in diffusion weighted images, leading to a set of unusable measurements. This is caused by bulk (subject or physiological) motion during the diffusion encoding part of the imaging sequence. We suggest a method to detect slices affected by signal loss and replace them by a non-parametric prediction, in order to minimise their impact on subsequent analysis. The outlier detection and replacement, as well as correction of other dMRI distortions (susceptibility-induced distortions, eddy currents (EC) and subject motion) are performed within a single framework, allowing the use of an integrated approach for distortion correction. Highly realistic simulations have been used to evaluate the method with respect to its ability to detect outliers (types 1 and 2 errors), the impact of outliers on retrospective correction of movement and distortion and the impact on estimation of commonly used diffusion tensor metrics, such as fractional anisotropy (FA) and mean diffusivity (MD). Data from a large imaging project studying older adults (the Whitehall Imaging sub-study) was used to demonstrate the utility of the method when applied to datasets with severe subject movement. The results indicate high sensitivity and specificity for detecting outliers and that their deleterious effects on FA and MD can be almost completely corrected. [ABSTRACT FROM AUTHOR]

In this paper we demonstrate a simulation framework that enables the direct and quantitative comparison of post-processing methods for diffusion weighted magnetic resonance (DW-MR) images. DW-MR datasets are employed in a range of techniques that enable estimates of local microstructure and global connectivity in the brain. These techniques require full alignment of images across the dataset, but this is rarely the case. Artefacts such as eddy-current (EC) distortion and motion lead to misalignment between images, which compromise the quality of the microstructural measures obtained from them. Numerous methods and software packages exist to correct these artefacts, some of which have become de-facto standards, but none have been subject to rigorous validation. In the literature, improved alignment is assessed using either qualitative visual measures or quantitative surrogate metrics. Here we introduce a simulation framework that allows for the direct, quantitative assessment of techniques, enabling objective comparisons of existing and future methods. DW-MR datasets are generated using a process that is based on the physics of MRI acquisition, which allows for the salient features of the images and their artefacts to be reproduced. We apply this framework in three ways. Firstly we assess the most commonly used method for artefact correction, FSL's eddy_correct, and compare it to a recently proposed alternative, eddy. We demonstrate quantitatively that using eddy_correct leads to significant errors in the corrected data, whilst eddy is able to provide much improved correction. Secondly we investigate the datasets required to achieve good correction with eddy, by looking at the minimum number of directions required and comparing the recommended full-sphere acquisitions to equivalent half-sphere protocols. Finally, we investigate the impact of correction quality by examining the fits from microstructure models to real and simulated data. [ABSTRACT FROM AUTHOR]

Abstract: Age and hypertension contribute significantly to cardiac morbidity and mortality, however the importance of each during the progression of hypertrophy is unclear. This investigation examined the effect of age and hypertension on Ca2+ handling in rat ventricular myocytes by comparing a genetic model of hypertension and cardiac hypertrophy (spontaneously hypertensive rat, SHR) with its normotensive control (Wistar–Kyoto rat, WKY) at 5 and 8 months of age. Experiments were performed on single left ventricular myocytes isolated from SHR or WKY hearts. Intracellular Ca2+ was measured optically using fura-2 or fluo-3. SHR myocytes had a significantly larger cell width and volume and a significantly decreased cell length/width ratio at 5 and 8 months compared to normotensive controls. Age had no effect on cell length, width, volume or the length/width ratio. Ca2+ transient amplitude, sarcoplasmic reticulum (SR) Ca2+ content and contraction amplitude were unaffected by age or hypertrophy. However at 8 months the contribution of the SR to Ca2+ uptake during relaxation decreased, with a concomitant increase in the contribution of Na+/Ca2+ exchanger (NCX) function to relaxation, in SHR and WKY myocytes. The incidence of non-synchronous SR Ca2+ release decreased with age but not hypertrophy in SHR and WKY myocytes. These results show that the changes in Ca2+ handling observed during progression of mild hypertrophy in SHR are the same as those that occur during ageing in normotensive control animals and can, therefore, be ascribed to maturation rather than hypertrophy. [Copyright &y& Elsevier]

Abstract: LIM kinase 1 (LIMK1) is a key regulator of actin dynamics as it phosphorylates and inactivates cofilin, an actin-depolymerizing factor. LIMK1 activity is also required for microtubule disassembly in endothelial cells. A search for LIMK1-interacting proteins identified p25α, a phosphoprotein that promotes tubulin polymerization. We found that p25 is phosphorylated by LIMK1 on serine residues in vitro and in cells. Immunoblotting analysis revealed that p25 is not a brain specific protein as previously reported, but is expressed in all mouse tissues. Immunofluorescence analysis demonstrated that endogenous p25 is co-localized with microtubules and is also found in the nucleus. Down-regulation of p25 by siRNA decreased microtubule levels while its overexpression in stable NIH-3T3 cell lines increased cell size and levels of stable tubulin. Bacterially expressed unphosphorylated p25 promotes microtubule assembly in vitro; however, when phosphorylated in cells, p25 lost its ability to assemble microtubule. Our results represent a surprising connection between the tubulin and the actin cytoskeleton mediated by LIMK1. We propose that the LIMK1 phosphorylation of p25 blocks p25 activity, thus promoting microtubule disassembly. [Copyright &y& Elsevier]

Leydig cell tumours (LCTs) are frequently observed during rodent carcinogenicity studies, however, the significance of this effect to humans remains a matter of debate. Many chemicals that produce LCTs also induce hepatic cytochromes P450 (CYPs), but it is unknown whether these two phenomena are causally related. Our aim was to investigate the existence of a liver–testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic–pituitary–testis axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats. Male Sprague-Dawley rats were dosed with lansoprazole (150 mg/kg/day) or vehicle for 14 days. Lansoprazole treatment produced effects on the liver consistent with an enhanced metabolic capacity, including significant increases in relative liver weights, total microsomal CYP content, individual CYP protein levels, and enhanced CYP-dependent testosterone metabolism in vitro. Following intravenous administration of [14C]testosterone, lansoprazole-treated rats exhibited a significantly smaller area under the curve and significantly higher plasma clearance. Significant reductions in plasma and testicular testosterone levels were observed, confirming the ability of this compound to perturb androgen homeostasis. No significant changes in plasma LH, FSH, or prolactin levels were detected under our experimental conditions. Lansoprazole treatment exerted no marked effects on testicular testosterone metabolism. In summary, lansoprazole treatment induced hepatic CYP-dependent testosterone metabolism in vitro and enhanced plasma clearance of radiolabelled testosterone in vivo. These effects may contribute to depletion of circulating testosterone levels and hence play a role in the mode of LCT induction in lansoprazole-treated rats. [Copyright &y& Elsevier]

SNAP-25, one of the three SNARE-proteins responsible for synaptic release, can be phosphorylated by Protein Kinase C on Ser-187, close to the fusion pore. In neuroendocrine cells, this phosphorylation event potentiates vesicle recruitment into releasable pools, whereas the consequences of phosphorylation for synaptic release remain unclear. We mutated Ser-187 and expressed two mutants (S187C and S187E) in the context of the SNAP-25B-isoform in SNAP-25 knockout glutamatergic autaptic neurons. Whole-cell patch clamp recordings were performed to assess the effect of Ser-187 phosphorylation on synaptic transmission. Blocking phosphorylation by expressing the S187C mutant did not affect synapse density, basic evoked or spontaneous neurotransmission, the readily-releasable pool size or its Ca2+-independent or Ca2+-dependent replenishment. Furthermore, it did not affect the response to phorbol esters, which activate PKC. Expressing S187C in the context of the SNAP-25A isoform also did not affect synaptic transmission. Strikingly, the – potentially phosphomimetic – mutant S187E reduced spontaneous release and release probability, with the largest effect seen in the SNAP-25B isoform, showing that a negative charge in this position is detrimental for neurotransmission, in agreement with electrostatic fusion triggering. During the course of our experiments, we found that higher SNAP-25B expression levels led to decreased paired pulse potentiation, probably due to higher release probabilities. Under these conditions, the potentiation of evoked EPSCs by phorbol esters was followed by a persistent down-regulation, probably due to a ceiling effect. In conclusion, our results indicate that phosphorylation of Ser-187 in SNAP-25 is not involved in modulation of synaptic release by Ca2+ or phorbol esters. • SNAP-25 is phosphorylated by protein kinase C at Ser-187. • Blocking phosphorylation of at Ser-187 does not change neurotransmission. • Phosphorylation of Ser-187 is not involved in phorbol ester dependent stimulation. • A negative charge placed at position 187 is detrimental for synaptic transmission. • Overexpression of SNAP-25 reduces the effect of phorbol esters on evoked release. [ABSTRACT FROM AUTHOR]