ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits

Achievements and Challenges in the Science of Space Weather

In June 2016 a group of 40 space weather scientists attended the workshop on Scientific Foundations of Space Weather at the International Space Science Institute in Bern. In this lead article to the volume based on the talks and discussions during the workshop we review some of main past achievements in the field and outline some of the challenges that the science of space weather is facing today and in the future.Peer reviewe

A ‘VISUAL’ APPROACH TO MENANDER - (A.K.) Petrides Menander, New Comedy and the Visual. Pp. xii + 322, ills. Cambridge: Cambridge University Press, 2014. Cased, £65, US$99. ISBN: 978-1-107-06843-8.

High-energy X-rays and gamma-rays from solar flares were discovered just over fifty years ago. Since that time, the standard for the interpretation of spatially integrated flare X-ray spectra at energies above several tens of keV has been the collisional thick-target model. After the launch of the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) in early 2002, X-ray spectra and images have been of sufficient quality to allow a greater focus on the energetic electrons responsible for the X-ray emission, including their origin and their interactions with the flare plasma and magnetic field. The result has been new insights into the flaring process, as well as more quantitative models for both electron acceleration and propagation, and for the flare environment with which the electrons interact. In this article we review our current understanding of electron acceleration, energy loss, and propagation in flares. Implications of these new results for the collisional thick-target model, for general flare models, and for future flare studies are discussed.Comment: This is an article from a monograph on the physics of solar flares, inspired by RHESSI observations. The individual articles are to appear in Space Science Reviews (2011

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies