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)

Is a Water Content of 60% Maximum Water Holding Capacity Suitable for Folsomia candida Reproduction Tests? A Study with Silver Nanoparticles and AgNO3

Silver nanoparticles (AgNP) are increasingly emitted to the environment due to a rise in application in various products; therefore, assessment of their potential risks for biota is important. In this study the effects of AgNP at environmentally relevant concentrations (0.6–375 µg kg−1 soil) on the soil invertebrate Folsomia candida in OECD (Organisation for Economic Co-operation and Development) soil was examined at different soil water contents. Animals were retrieved by heat extraction, which had an efficiency of about 90% compared with the floatation method. The tested water content range is set by OECD Guideline 232 (40–60% of the maximum water holding capacity, WHC), and we detected significant differences in toxicity due to these. With AgNO3, used as an ionic control, the number of juveniles significantly decreased only at 40% WHC, which might be due to dilution of the toxicant at higher soil water content. In turn, at 60% WHC, the reproduction of F. candida significantly increased in the presence of AgNP compared with in the control. However, at this water content, the required number of juveniles in the control treatment was not reached in three independent tests. The fact that the OECD validity criterion is not met indicates that the soil conditions are not suitable for reproduction at 60% WHC

Collembola Reproduction Decreases with Aging of Silver Nanoparticles in a Sewage Sludge-Treated Soil

Silver nanoparticles (AgNP) are integrated into various products due to their antimicrobial characteristics and hence, the application of AgNP is increasing. During production, use and disposal AgNP are emitted and enter the environment via several pathways. Soils are considered a major sink of AgNP. The aim of the present study was to determine the toxic effect of AgNP on Folsomia candida reproduction to illustrate potential impact on terrestrial ecosystems. The AgNP-dependent reduction of F. candida reproduction was studied in RefeSol 01-A, LUFA 2.2 and OECD soil at 0.3 μg–50 mg Ag kg−1. To simulate realistic exposure pathways, effects on F. candida reproduction after the application of AgNP via sewage sludge and after aging this treatment in the soil for up to 140 days were studied using environmentally relevant concentrations. The OECD representative AgNP, NM-300K, and AgNO3, as a metal salt reference, were used in all experiments. The generated data demonstrate that the presence of AgNP in the soil in the low mg Ag kg−1 concentration range results in significant, but concentration independent inhibition of F. candida reproduction in RefeSol 01-A and LUFA 2.2. Significant inhibition of F. candida reproduction due to AgNP was also observed for soil amended with AgNP treated sludge. An increase in inhibition with aging of the AgNP in the soil was evident. In conclusion, our results demonstrate that, at environmentally relevant concentrations, AgNP adsorption to sludge and subsequent aging in soil lead to a toxic effect on soil invertebrates

Nanoparticles in the environment: where do we come from, where do we go to?

Abstract Nanoparticles serve various industrial and domestic purposes which is reflected in their steadily increasing production volume. This economic success comes along with their presence in the environment and the risk of potentially adverse effects in natural systems. Over the last decade, substantial progress regarding the understanding of sources, fate, and effects of nanoparticles has been made. Predictions of environmental concentrations based on modelling approaches could recently be confirmed by measured concentrations in the field. Nonetheless, analytical techniques are, as covered elsewhere, still under development to more efficiently and reliably characterize and quantify nanoparticles, as well as to detect them in complex environmental matrixes. Simultaneously, the effects of nanoparticles on aquatic and terrestrial systems have received increasing attention. While the debate on the relevance of nanoparticle-released metal ions for their toxicity is still ongoing, it is a re-occurring phenomenon that inert nanoparticles are able to interact with biota through physical pathways such as biological surface coating. This among others interferes with the growth and behaviour of exposed organisms. Moreover, co-occurring contaminants interact with nanoparticles. There is multiple evidence suggesting nanoparticles as a sink for organic and inorganic co-contaminants. On the other hand, in the presence of nanoparticles, repeatedly an elevated effect on the test species induced by the co-contaminants has been reported. In this paper, we highlight recent achievements in the field of nano-ecotoxicology in both aquatic and terrestrial systems but also refer to substantial gaps that require further attention in the future