Flow rate impacts on capillary pressure and interface curvature of connected and disconnected fluid phases during multiphase flow in sandstone

We investigate capillary pressure-saturation (PC-S) relationships for drainage-imbibition experiments conducted with air (nonwetting phase) and brine (wetting phase) in Bentheimer sandstone cores. Three different flow rate conditions, ranging over three orders of magnitude, are investigated. X-ray micro-computed tomographic imaging is used to characterize the distribution and amount of fluids and their interfacial characteristics. Capillary pressure is measured via (1) bulk-phase pressure transducer measurements, and (2) image-based curvature measurements, calculated using a novel 3D curvature algorithm. We distinguish between connected (percolating) and disconnected air clusters: curvatures measured on the connected phase interfaces are used to validate the curvature algorithm and provide an indication of the equilibrium condition of the data; curvature and volume distributions of disconnected clusters provide insight to the snap-off processes occurring during drainage and imbibition under different flow rate conditionsWe gratefully acknowledge funding from the Australian Research Council through Discovery Project DP160104995, and the member companies of the ANU/UNSW Digicore Research Consortium

Techniques in helical scanning, dynamic imaging and image segmentation for improved quantitative analysis with X-ray micro-CT

This paper reports on recent advances at the micro-computed tomography facility at the Australian National University. Since 2000 this facility has been a significant centre for developments in imaging hardware and associated software for image reconstruction, image analysis and image-based modelling. In 2010 a new instrument was constructed that utilises theoretically-exact image reconstruction based on helical scanning trajectories, allowing higher cone angles and thus better utilisation of the available X-ray flux. We discuss the technical hurdles that needed to be overcome to allow imaging with cone angles in excess of 60°. We also present dynamic tomography algorithms that enable the changes between one moment and the next to be reconstructed from a sparse set of projections, allowing higher speed imaging of time-varying samples. Researchers at the facility have also created a sizeable distributed-memory image analysis toolkit with capabilities ranging from tomographic image reconstruction to 3D shape characterisation. We show results from image registration and present some of the new imaging and experimental techniques that it enables. Finally, we discuss the crucial question of image segmentation and evaluate some recently proposed techniques for automated segmentation

Creation and confidence: BME students as academic partners…but where were the staff?

This Case Study documents the REACT project 'Creation and Confidence' based at Sheffield Hallam University, which has a larger-than-expected Black Minority and Ethnic (BME) attainment gap; hence, this student group has been constructed as 'hard to reach'. The project team consisted of a range of academic and professional services staff alongside three dedicated student researchers. The project set out to achieve: gaining evidence-based insights into the use of co-design and peer-learning as conduits of confidence-building for and belonging of BME students; developing a scalable approach to building confidence for and fostering belonging of all students; raising awareness of the need to think differently about explanations for BME underachievement. In reality, the team found that staff engagement constituted the biggest barrier, as - no matter how much incontrovertible evidence was presented - other facets of institutional provision were always identified as having priority, which resulted in inertia. This study documents the emotional labour of trying to effect change within a resistant culture. Whilst some of the aims remain unachieved – and, arguably, were always going to be unachievable - there have been some very positive developments and enlightening lessons

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)