Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Postnatal ExErcise Partners Study (PEEPS): A Pilot Randomised Trial of a Dyadic Physical Activity Intervention for Postpartum Mothers and a Significant Other

Research suggests dyadic interventions can increase physical activity; such interventions are untested within postpartum parent couples. A three-armed pilot randomised trial addressed this gap and tested which type of dyadic intervention is most effective. Inactive postpartum mothers and a significant other were recruited in Australia (n = 143 assessed for eligibility) and randomised in a single-blinded fashion (i.e., participants were blinded) to 1 of 3 dyadic conditions involving a single face-to-face session with access to web-based group support: a minimal treatment control (n = 34), collaborative planning group (n = 38), or collaborative planning + need supportive communication group (n = 30). Participants were asked to wear their accelerometers for 8 days and completed self-report measures at baseline, end of intervention (week 4), and follow-up (week 12). We expected dyads in the collaborative planning + need supportive communication group would have the greatest increases in Physical Activity (PA), autonomous motivation, and partners’ need supportive behaviours; and decreases in controlled motivation and controlling partner behaviours. Results from 51 dyads using Bayesian actor-partner interdependence models provided some evidence for a small positive effect on total physical activity at follow-up for postpartum mothers in the collaborative planning group and for partners in the collaborative planning + need supportive communication group. Furthermore, partners in the collaborative planning + need supportive communication group were more likely to engage in some vigorous PA. At follow-up, postpartum mothers in the collaborative planning + need supportive communication group scored lower on personal autonomous reasons. The impact of prior specification mean intervention effects need to be interpreted with caution. Progression to a full trial is warranted. Keywords: Postpartum, Mothers, Dyads, Randomized controlled trial, Physical activity. This project was funded by a Curtin International Postgraduate Research Scholarship/ Health Sciences Faculty International Research Scholarship. Andreas Stenling was supported by an international postdoc grant from the Swedish Research Council (dnr: 2017-00273)

High School Students' Proficiency and Confidence Levels in Displaying Their Understanding of Basic Electrolysis Concepts

This study was conducted with 330 Form 4 (grade 10) students (aged 15 – 16 years) who were involved in a course of instruction on electrolysis concepts. The main purposes of this study were (1) to assess high school chemistry students’ understanding of 19 major principles of electrolysis using a recently developed 2-tier multiple-choice diagnostic instrument, the Electrolysis Diagnostic Instrument (EDI), and (2) to assess students’ confidence levels in displaying their knowledge and understanding of these electrolysis concepts. Analysis of students’ responses to the EDI showed that they displayed very limited understanding of the electrolytic processes involving molten compounds and aqueous solutions of compounds, with a mean score of 6.82 (out of a possible maximum of 17). Students were found to possess content knowledge about several electrolysis processes but did not provide suitable explanations for the changes that had occurred, with less than 45 % of students displaying scientifically acceptable understandings about electrolysis. In addition, students displayed limited confidence about making the correct selections for the items; yet, in 16 of the 17 items, the percentage of students who were confident that they had selected the correct answer to an item was higher than the actual percentage of students who correctly answered the corresponding item. The findings suggest several implications for classroom instruction on the electrolysis topic that need to be addressed in order to facilitate better understanding by students of electrolysis concepts

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population

The initial GWAS was funded by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a non-profit organization dedicated to identifying and validating DNA variants useful in predicting the risk of drug-related serious adverse events. The Consortium brings together the pharmaceutical industry, regulatory authorities and academic centres to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC’s current funding members include: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda and the Wellcome Trust. Mas Chaponda was funded by a 3 year Wellcome Trust training fellowship WT078857MA administered through the University of Liverpool. Malawi-Liverpool-Wellcome Trust Clinical Research Programme is funded through a Core Programme Grant award from the Wellcome Trust. Munir Pirmohamed is a National Institute for Health Research Senior Investigator, and also wishes to thank the MRC Centre for Drug Safety Science for support. The DART study was supported by the UK Medical Research Council (grant number G0600344), the UK Department for International Development and the Rockefeller Foundation. Andrew P. Morris is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Louise Y. Takeshita is funded by a PhD fellowship from CNPq (National Council for Scientific and Technological Development, Brazil). Panos Deloukas’ work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research

Susceptibility and Response of Human Blood Monocyte Subsets to Primary Dengue Virus Infection

Human blood monocytes play a central role in dengue infections and form the majority of virus infected cells in the blood. Human blood monocytes are heterogeneous and divided into CD16− and CD16+ subsets. Monocyte subsets play distinct roles during disease, but it is not currently known if monocyte subsets differentially contribute to dengue protection and pathogenesis. Here, we compared the susceptibility and response of the human CD16− and CD16+ blood monocyte subsets to primary dengue virus in vitro. We found that both monocyte subsets were equally susceptible to dengue virus (DENV2 NGC), and capable of supporting the initial production of new infective virus particles. Both monocyte subsets produced anti-viral factors, including IFN-α, CXCL10 and TRAIL. However, CD16+ monocytes were the major producers of inflammatory cytokines and chemokines in response to dengue virus, including IL-1β, TNF-α, IL-6, CCL2, 3 and 4. The susceptibility of both monocyte subsets to infection was increased after IL-4 treatment, but this increase was more profound for the CD16+ monocyte subset, particularly at early time points after virus exposure. These findings reveal the differential role that monocyte subsets might play during dengue disease

HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme