A spontaneous increase in intracellular Ca2+ in metaphase II human oocytes in vitro can be prevented by drugs targeting ATP-sensitive K+ channels

STUDY QUESTION: Could drugs targeting ATP-sensitive K+ (KATP) channels prevent any spontaneous increase in intracellular Ca2+ that may occur in human metaphase II (MII) oocytes under in vitro conditions? SUMMARY ANSWER: Pinacidil, a KATP channel opener, and glibenclamide, a KATP channel blocker, prevent a spontaneous increase in intracellular Ca2+ in human MII oocytes. WHAT IS KNOWN ALREADY: The quality of the oocyte and maintenance of this quality during in vitro processing in the assisted reproductive technology (ART) laboratory is of critical importance to successful embryo development and a healthy live birth. Maintenance of Ca2+ homeostasis is crucial for cell wellbeing and increased intracellular Ca2+ levels is a well-established indicator of cell stress. STUDY DESIGN, SIZE, DURATION: Supernumerary human oocytes (n = 102) collected during IVF/ICSI treatment that failed to fertilize were used from October 2013 to July 2015. All experiments were performed on mature (MII) oocytes. Dynamics of intracellular Ca2+ levels were monitored in oocytes in the following experimental groups: (i) Control, (ii) Dimethyl sulfoxide (DMSO; used to dissolve pinacidil, glibenclamide and 2,4-Dinitrophenol (DNP)), (iii) Pinacidil, (iv) Glibenclamide, (v) DNP: an inhibitor of oxidative phosphorylation, (vi) Pinacidil and DNP and (vii) Glibenclamide and DNP. PARTICIPANTS/MATERIALS/SETTINGS/METHODS: Oocytes were collected under sedation as part of routine treatment at an assisted conception unit from healthy women (mean ± SD) age 34.1 ± 0.6 years, n = 41. Those surplus to clinical use were donated for research. Oocytes were loaded with Fluo-3 Ca2+-sensitive dye, and monitored by laser confocal microscopy for 2 h at 10 min intervals. Time between oocyte collection and start of Ca2+ monitoring was 80.4 ± 2.1 h. MAIN RESULTS AND THE ROLE OF CHANCE: Intracellular levels of Ca2+ increased under in vitro conditions with no deliberate challenge, as shown by Fluo-3 fluorescence increasing from 61.0 ± 11.8 AU (AU = arbitrary units; n = 23) to 91.8 ± 14.0 AU (n = 19; P <0.001) after 2 h of monitoring. Pinacidil (100 µM) inhibited this increase in Ca2+ (85.3 ± 12.3 AU at the beginning of the experiment, 81.7 ± 11.0 AU at the end of the experiment; n = 13; P = 0.616). Glibenclamide (100 µM) also inhibited the increase in Ca2+ (74.7 ± 10.6 AU at the beginning and 71.8 ± 10.9 AU at the end of the experiment; n = 13; P = 0.851. DNP (100 mM) induced an increase in intracellular Ca2+ that was inhibited by glibenclamide (100 µM; n = 9) but not by pinacidil (100 µM; n = 5). LIMITATIONS, REASONS FOR CAUTION: Owing to clinical and ethical considerations, it was not possible to monitor Ca2+ in MII oocytes immediately after retrieval. MII oocytes were available for our experimentation only after unsuccessful IVF or ICSI, which was, on average, 80.4 ± 2.1 h (n = 102 oocytes) after the moment of retrieval. As the MII oocytes used here were those that were not successfully fertilized, it is possible that they may have been abnormal with impaired Ca2+ homeostasis and, furthermore, the altered Ca2+ homeostasis might have been associated solely with the protracted incubation. WIDER IMPLICATIONS OF THE FINDINGS: These results show that maintenance of oocytes under in vitro conditions is associated with intracellular increase in Ca2+, which can be counteracted by drugs targeting KATP channels. As Ca2+ homeostasis is crucial for contributing to a successful outcome of ART, these results suggest that KATP channel openers and blockers should be tested as drugs for improving success rates of ART

Intraoperative Organ Motion Models with an Ensemble of Conditional Generative Adversarial Networks

In this paper, we describe how a patient-specific, ultrasound-probe-induced prostate motion model can be directly generated from a single preoperative MR image. Our motion model allows for sampling from the conditional distribution of dense displacement fields, is encoded by a generative neural network conditioned on a medical image, and accepts random noise as additional input. The generative network is trained by a minimax optimisation with a second discriminative neural network, tasked to distinguish generated samples from training motion data. In this work, we propose that 1) jointly optimising a third conditioning neural network that pre-processes the input image, can effectively extract patient-specific features for conditioning; and 2) combining multiple generative models trained separately with heuristically pre-disjointed training data sets can adequately mitigate the problem of mode collapse. Trained with diagnostic T2-weighted MR images from 143 real patients and 73,216 3D dense displacement fields from finite element simulations of intraoperative prostate motion due to transrectal ultrasound probe pressure, the proposed models produced physically-plausible patient-specific motion of prostate glands. The ability to capture biomechanically simulated motion was evaluated using two errors representing generalisability and specificity of the model. The median values, calculated from a 10-fold cross-validation, were 2.8+/-0.3 mm and 1.7+/-0.1 mm, respectively. We conclude that the introduced approach demonstrates the feasibility of applying state-of-the-art machine learning algorithms to generate organ motion models from patient images, and shows significant promise for future research.Comment: Accepted to MICCAI 201

Adversarial Deformation Regularization for Training Image Registration Neural Networks

We describe an adversarial learning approach to constrain convolutional neural network training for image registration, replacing heuristic smoothness measures of displacement fields often used in these tasks. Using minimally-invasive prostate cancer intervention as an example application, we demonstrate the feasibility of utilizing biomechanical simulations to regularize a weakly-supervised anatomical-label-driven registration network for aligning pre-procedural magnetic resonance (MR) and 3D intra-procedural transrectal ultrasound (TRUS) images. A discriminator network is optimized to distinguish the registration-predicted displacement fields from the motion data simulated by finite element analysis. During training, the registration network simultaneously aims to maximize similarity between anatomical labels that drives image alignment and to minimize an adversarial generator loss that measures divergence between the predicted- and simulated deformation. The end-to-end trained network enables efficient and fully-automated registration that only requires an MR and TRUS image pair as input, without anatomical labels or simulated data during inference. 108 pairs of labelled MR and TRUS images from 76 prostate cancer patients and 71,500 nonlinear finite-element simulations from 143 different patients were used for this study. We show that, with only gland segmentation as training labels, the proposed method can help predict physically plausible deformation without any other smoothness penalty. Based on cross-validation experiments using 834 pairs of independent validation landmarks, the proposed adversarial-regularized registration achieved a target registration error of 6.3 mm that is significantly lower than those from several other regularization methods.Comment: Accepted to MICCAI 201

C Wright Mills, power and the power elites ? a reappraisal

This paper revisits and presents a critical appraisal of Mills's analysis of power and the power elite. There are signs of a revival of interest in Mills, but recent commentators have shown little interest in the intellectual, social or political context of his analysis. Setting Mills's thesis in its historical context, we consider an element of his project that has been particularly neglected in recent discussion: Mills's search for possible ways of redistributing power and his attempt to forge an ethico-political stance. Reflecting on recent discussion of contemporary elite formations, we comment on what critics might take from Mills in our own time in relation to the analysis of elites and the politics of critical management studies

Rayleigh-B\'{e}nard convection in a homeotropically aligned nematic liquid crystal

We report experimental results for convection near onset in a thin layer of a homeotropically aligned nematic liquid crystal heated from below as a function of the temperature difference $\Delta T$ and the applied vertical magnetic field $H$ and compare them with theoretical calculations. The experiments cover the field range 8 \alt h \equiv H/ H_{F} \alt 80 ($H_F =$ is the Fr\'eedericksz field). For $h$ less than a codimension-two field $h_{ct} \simeq 46$ the bifurcation is subcritical and oscillatory, with travelling- and standing-wave transients. Beyond $h_{ct}$ the bifurcation is stationary and subcritical until a tricritical field $h_t= 57.2$ is reached, beyond which it is supercritical. The bifurcation sequence as a function of $h$ found in the experiment confirms the qualitative aspects of the theoretical predictions. However, the value of $h_{ct}$ is about 10% higher than the predicted value and the results for $k_c$ are systematically below the theory by about 2% at small $h$ and by as much as 7% near $h_{ct}$. At $h_{ct}$, $k_c$ is continuous within the experimental resolution whereas the theory indicates a 7% discontinuity. The theoretical tricritical field $h_t^{th} = 51$ is somewhat below the experimental one. The fully developed flow above $R_c$ for $h < h_{ct}$ is chaotic. For $h_{ct} < h < h_t$ the subcritical stationary bifurcation also leads to a chaotic state. The chaotic states persist upon reducing the Rayleigh number below $R_c$, i.e. the bifurcation is hysteretic. Above the tricritical field $h_t$, we find a bifurcation to a time independent pattern which within our resolution is non-hysteretic.Comment: 15 pages incl. 23 eps figure

Selective aortic arch perfusion: a first-in-human observational cadaveric study.

BACKGROUND: Selective aortic arch perfusion (SAAP) is a novel endovascular technique that combines thoracic aortic occlusion with extracorporeal perfusion of the brain and heart. SAAP may have a role in both haemorrhagic shock and in cardiac arrest due to coronary ischaemia. Despite promising animal studies, no data is available that describes SAAP in humans. The primary aim of this study was to assess the feasibility of selective aortic arch perfusion in humans. The secondary aim of the study was to assess the feasibility of achieving direct coronary artery access via the SAAP catheter as a potential conduit for salvage percutaneous coronary intervention. METHODS: Using perfused human cadavers, a prototype SAAP catheter was inserted into the descending aorta under fluoroscopic guidance via a standard femoral percutaneous access device. The catheter balloon was inflated and the aortic arch perfused with radio-opaque contrast. The coronary arteries were cannulated through the SAAP catheter. RESULTS: The procedure was conducted four times. During the first two trials the SAAP catheter was passed rapidly and without incident to the intended descending aortic landing zone and aortic arch perfusion was successfully delivered via the device. The SAAP catheter balloon failed on the third trial. On the fourth trial the left coronary system was cannulated using a 5Fr coronary guiding catheter through the central SAAP catheter lumen. CONCLUSIONS: For the first time using a perfused cadaveric model we have demonstrated that a SAAP catheter can be easily and safely inserted and SAAP can be achieved using conventional endovascular techniques. The SAAP catheter allowed successful access to the proximal aorta and permitted retrograde perfusion of the coronary and cerebral circulation

Single-cell analysis of [Ca²⁺]i signalling in sub-fertile men:characteristics and relation to fertilization outcome

STUDY QUESTIONWhat are the characteristics of progesterone-induced (CatSper-mediated) single cell [Ca2+]i signals in spermatozoa from sub-fertile men and how do they relate to fertilizing ability?SUMMARY ANSWERSingle cell analysis of progesterone-induced (CatSper-mediated) [Ca2+]i showed that reduced progesterone-sensitivity is a common feature of sperm from sub-fertile patients and is correlated with fertilization rate.WHAT IS KNOWN ALREADYStimulation with progesterone is a widely used method for assessing [Ca2+]i mobilization by activation of CatSper in human spermatozoa. Although data are limited, sperm population studies have indicated an association of poor [Ca2+]i response to progesterone with reduced fertilization ability.STUDY DESIGN, SIZE, DURATIONThis was a cohort study using semen samples from 21 donors and 101 patients attending the assisted conception unit at Ninewells Hospital Dundee who were undergoing ART treatment. Patients were recruited from January 2016 to June 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSSemen donors and patients were recruited in accordance with local ethics approval (13/ES/0091) from the East of Scotland Research Ethics Service (EoSRES) REC1. [Ca2+]i responses were examined by single cell imaging and motility parameters assessed by computer-assisted sperm analysis (CASA).MAIN RESULTS AND THE ROLE OF CHANCEFor analysis, patient samples were divided into three groups IVF(+ve) (successful fertilization; 62 samples), IVF-FF (failed fertilization; eight samples) and ICSI (21 samples). A further 10 IVF samples showed large, spontaneous [Ca2+]i oscillations and responses to progesterone could not be analysed. All patient samples loaded with the [Ca2+]i-indicator fluo4 responded to progesterone stimulation with a biphasic increase in fluorescence (transient followed by plateau) which resembled that seen in progesterone-stimulated donor samples. The mean normalized response (progesterone-induced increase in fluorescence normalized to resting level) was significantly smaller in IVF-FF and ICSI patient groups than in donors. All samples were further analysed by plotting, for each cell, the relationship between resting fluorescence intensity and the progesterone-induced fluorescence increment. In donor samples these plots overlaid closely and had a gradient of ≈ 2 and plots for most IVF(+ve) samples closely resembled the donor distribution. However, in a subset (≈ 10%) of IVF(+ve) samples, 3/8 IVF-FF samples and one-third of ICSI samples the gradient of the plot was significantly lower, indicating that the response to progesterone of the cells in these samples was abnormally small. Examination of the relationship between gradient (regression coefficient of the plot) in IVF samples and fertilization rate showed a positive correlation. In IVF-FF and ICSI groups, the proportion of cells in which a response to progesterone could be detected was significantly lower than in donors and IVF (+ve) patients. Approximately 20% of cells in donor, IVF(+ve) and ICSI samples generated [Ca2+]i oscillations when challenged with progesterone but in IVF-FF samples only ≈ 10% of cells generated oscillations and there was a significantly greater proportion of samples where no oscillations were observed. Levels of hyperactivated motility were lower in IVF(+ve) and IVF-FF groups compared to controls, IVF-FF also having lower levels than IVF(+ve).LIMITATIONS, REASONS FOR CAUTIONThis is an in vitro study and caution must be taken when extrapolating these results in vivo.WIDER IMPLICATIONS OF THE FINDINGSThis study reveals important details of impaired [Ca2+]i signalling in sperm from sub-fertile men that cannot be detected in population studies

Label-driven weakly-supervised learning for multimodal deformable image registration

Spatially aligning medical images from different modalities remains a challenging task, especially for intraoperative applications that require fast and robust algorithms. We propose a weakly-supervised, label-driven formulation for learning 3D voxel correspondence from higher-level label correspondence, thereby bypassing classical intensity-based image similarity measures. During training, a convolutional neural network is optimised by outputting a dense displacement field (DDF) that warps a set of available anatomical labels from the moving image to match their corresponding counterparts in the fixed image. These label pairs, including solid organs, ducts, vessels, point landmarks and other ad hoc structures, are only required at training time and can be spatially aligned by minimising a cross-entropy function of the warped moving label and the fixed label. During inference, the trained network takes a new image pair to predict an optimal DDF, resulting in a fully-automatic, label-free, real-time and deformable registration. For interventional applications where large global transformation prevails, we also propose a neural network architecture to jointly optimise the global- and local displacements. Experiment results are presented based on cross-validating registrations of 111 pairs of T2-weighted magnetic resonance images and 3D transrectal ultrasound images from prostate cancer patients with a total of over 4000 anatomical labels, yielding a median target registration error of 4.2 mm on landmark centroids and a median Dice of 0.88 on prostate glands.Comment: Accepted to ISBI 201

Parallel quantum simulation of large systems on small NISQ computers

Tensor networks permit computational and entanglement resources to be concentrated in interesting regions of Hilbert space. Implemented on NISQ machines they allow simulation of quantum systems that are much larger than the computational machine itself. This is achieved by parallelising the quantum simulation. Here, we demonstrate this in the simplest case; an infinite, translationally invariant quantum spin chain. We provide Cirq and Qiskit code that translates infinite, translationally invariant matrix product state (iMPS) algorithms to finite-depth quantum circuit machines, allowing the representation, optimisation and evolution of arbitrary one-dimensional systems. The illustrative simulated output of these codes for achievable circuit sizes is given