A frameshift-deletion mutation in Reelin causes cerebellar hypoplasia in White Swiss Shepherd dogs.

Cerebellar hypoplasia is a heterogeneous neurological condition in which the cerebellum is smaller than usual or not completely developed. The condition can have genetic origins, with Mendelian-effect mutations described in several mammalian species. Here, we describe a genetic investigation of cerebellar hypoplasia in White Swiss Shepherd dogs, where two affected puppies were identified from a litter with a recent common ancestor on both sides of their pedigree. Whole genome sequencing was conducted for 10 dogs in this family, and filtering of these data based on a recessive transmission hypothesis highlighted five protein-altering candidate variants - including a frameshift-deletion of the Reelin (RELN) gene (p.Val947*). Given the status of RELN as a gene responsible for cerebellar hypoplasia in humans, sheep and mice, these data strongly suggest the loss-of-function variant as underlying these effects. This variant has not been found in other dog breeds nor in a cohort of European White Swiss Shepherds, suggesting a recent mutation event. This finding will support the genotyping of a more diverse sample of dogs, and should aid future management of the harmful allele through optimised mating schemes

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)

A first look at ILOOC

This paper will be an interim report on the ILOOC project at the University of Northampton. The authors have designed a CPD course which is designed to open up accessibility on LLM courses for non-law graduates. The CPD offer is a non-credit-bearing course, which will be delivered 100 per cent online, comprises 4 distinct units. One of these, which focuses on International Law will form ILOOC (International Law Open Online Content). ILOOC is designed so that it can be studied as a stand-alone unit, or form part of the full CPD

Legal Frameworks

In many ways, the production, ownership and transfer of firearms is regulated in the same way as the production, ownership and transfer of any other commodity, but the regulations have always been tighter when concerning firearms.  Earlier in this book, we saw that both the legal and illicit manufacturing, acquisition, trafficking and criminal misuse all physically take place on the soil of a sovereign State. This means that that State must develop regulations and laws designed to prevent or reduce these illicit activities. Modern national legal frameworks are constructed under the umbrella of different extra-national legislative measures that have been developed to prevent and reduce illicit activities involving firearms. However, as this chapter will demonstrate, these instruments are generally of a guiding nature, and will not be successful unless States implement the regulations and policies agreed to in the instruments. The chapter will discuss the development of these supra-national frameworks, and consider how States develop these regulations and measures. It will cover elements such as stockpile management, purchasing and ownership restrictions, law enforcement and standards on collecting and destroying firearms. For reach of the supranational elements, examples will be given of how these are put into place at a national level

International Law Open Online Course (ILOOC)

The International Law (M)OOC (ILOOC) from the University of Northampton does not require users to have had any previous experience or practice in International Law. It is intended to give a flavour of the topic, and to provide a foundation upon which further study in the area may be built. At the University of Northampton we partly use ILOOC as the “MOOC” part of a wider CPD course, which gives access to our LLM (Master of Laws) courses. The course is available as a MOOC on Coursesites (http://bit.ly/ILOOC-Site), free of charge for any learner to enrol and participate. This ZIP file contains the main course content and can be directly transferred into a Learning Management System (LMS) that supports the IMS/SCORM import. This file has been tested on Blackboard 9.1 and Desire2Learn, but should import into many others. Source data for the formative tests is also included. The content of the ZIP file is not encrypted or obfuscated, so individual items can also extracted manually if required.

The impact on students of online and blended learning methods

This paper will draw upon two projects which consider the impact of different types of blended learning activities on student experience. One project takes two final year law modules and transforms parts of them into online, digitally-enhanced sessions using Blackboard Collaborate and other e-tivity methods. One module took a 6-week section of the content and enhanced face-to-face sessions with online sessions, and the other took discrete weeks and ran synchronous online sessions using Blackboard Collaborate. This project will analyse the levels of student engagement and satisfaction with these methods, compared to traditional classroom based delivery. It will also assess, as far as is practicable, the impact that this digital transformation has on different equality characteristics. The second project looks at a subject-wide innovation in 2015, whereby all the timetabled activities for one week were replaced with blended and online activities. The important difference of this second project is that the research is being designed and carried out by an undergraduate law student. The student researcher will also seek feedback from students on the blended learning activities in project one and this paper will investigate the extent to which students give different responses to another student to those they gave to the tutors. The results of both projects will feed forward into the development of a fully blended delivery of law programmes that are enabling for our students while valuing diversity

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

An amendment to this paper has been published and can be accessed via a link at the top of the paper