2.2 Validation of the 22-day Honey Bee Larval Toxicity, Repeated (Chronic) Exposure Study Design

Assessing the chronic toxicity of a compound to developing honey bees (Apis mellifera L.) has proven to be a challenge since the mid-2000s. Such data are requested by global regulatory authorities so they can evaluate the risk of compounds to larval honey bees when exposure is likely to occur in the environment. Poor test performance has led to frequent study failures and data uncertainty. Here we highlight a recent effort by the Pollinator Research Task Force (PRTF)1 to validate the use of a method for evaluating the chronic toxicity of a compound (e.g., a pesticide) to an immature honey bee for use in a risk assessment. A ring test protocol was selected and based upon the current OECD guidance document No. 2392 with amendments developed at the University of Florida (Schmehl et al. 2016)3. Fifteen independent laboratories on three continents representing government, academia, and industry followed the same testing protocol to: 1) determine if test performance is robust across different geographic regions and different laboratory personnel and 2) identify limitations associated with the methodology. The control performance criteria for a valid test according to OECD GD 239 is ≥ 85% survival at the end of the larval development and ≥ 70% survival through adult emergence. Thirteen trials (81.3%) satisfied the validity criteria and the test design’s performance was determined adequate for regulatory testing. The toxic reference chemical (dimethoate) had a consistent response with a 22-day EC 50 range of 8-22 μg active substance (a.s.)/g diet. An acetone concentration at the maximum concentration allowed by the OECD GD 239 (2% acetone) was observed to be problematic to test performance. In conclusion, the ring test methods based upon the OECD GD 239 demonstrated that the repeat (chronic) exposure of a compound on developing bees can be successfully conducted. A copy of the full study report4 can be accessed here.Assessing the chronic toxicity of a compound to developing honey bees (Apis mellifera L.) has proven to be a challenge since the mid-2000s. Such data are requested by global regulatory authorities so they can evaluate the risk of compounds to larval honey bees when exposure is likely to occur in the environment. Poor test performance has led to frequent study failures and data uncertainty. Here we highlight a recent effort by the Pollinator Research Task Force (PRTF)1 to validate the use of a method for evaluating the chronic toxicity of a compound (e.g., a pesticide) to an immature honey bee for use in a risk assessment. A ring test protocol was selected and based upon the current OECD guidance document No. 2392 with amendments developed at the University of Florida (Schmehl et al. 2016)3. Fifteen independent laboratories on three continents representing government, academia, and industry followed the same testing protocol to: 1) determine if test performance is robust across different geographic regions and different laboratory personnel and 2) identify limitations associated with the methodology. The control performance criteria for a valid test according to OECD GD 239 is ≥ 85% survival at the end of the larval development and ≥ 70% survival through adult emergence. Thirteen trials (81.3%) satisfied the validity criteria and the test design’s performance was determined adequate for regulatory testing. The toxic reference chemical (dimethoate) had a consistent response with a 22-day EC 50 range of 8-22 μg active substance (a.s.)/g diet. An acetone concentration at the maximum concentration allowed by the OECD GD 239 (2% acetone) was observed to be problematic to test performance. In conclusion, the ring test methods based upon the OECD GD 239 demonstrated that the repeat (chronic) exposure of a compound on developing bees can be successfully conducted. A copy of the full study report4 can be accessed here

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

Dystonia; Parkinson's disease/Parkinsonism; Genetic linkageMalaltia de Parkinson/Parkinsonisme; Vinculació genètica; DistoniaEnfermedad de Parkinson/Parkinsonismo; Enlace genético; DistoníaThis work was supported by the Health Institute Carlos III—General Subdirectorate for Research Evaluation and Promotion (PI16/01575, PI18/01898, PI18/00147, PI19/01576), the Spanish Ministry of Economy and Competitiveness (SAF2007-60700), the Ministry of Economy, Innovation, Science and Business of the Government of Andalucía (CVI-02526, CTS-7685), the Ministry of Health and Social Welfare of the Government of Andalucía (PI-0459-2018, PE-0210-2018, PE-0186-2019) and by the Valencian Government (PROMETEO/2018/135), within the framework of the National Research and Development Plan co-funded with European Regional Development Funds. Part of the equipment employed in this study was funded by the Valencian Government and co-financed with European Regional Development Funds (OP ERDF of Valencian Community 2014-2020). I. Hinarejos has a PFIS-PhD fellowship (FI19/00072), S. Jesús has a contract “Acción B Clínicos-Investigadores” (Action B Clinicians-Researchers) contract (B-0007-2019) funded by the Ministry of Health and Family of the Government of Andalucía, and D. Macías-García has a Río Hortega contract (CM18/00142) funded by the Health Institute Carlos III

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

TheNR4A2/NURR1gene (MIM*601828) has recently been associated with autosomal-dominantearly-onset dystonia-parkinsonism with intellectual disability.1NR4A2codifies for a nuclear tran-scription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbicareas.2To date, 14 different alterations inNR4A2have been described associated with variousclinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome(DPS) with motor tics, which expands the clinical phenotype ofNR4A2-associated DPS

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

26 páginas, 4 figuras, 3 tablasOur clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.This work was supported by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R + D+I Plan co-funded with European Regional Development Funds (ERDF) [Grants PI18/00147 and PI21/00103 to CE]; the Fundació La Marató TV3 [Grants 20143130 and 20143131 to BPD and CE]; and by the Generalitat Valenciana [Grant PROMETEO/2018/135 to CE]. Part of the equipment employed in this work was funded by Generalitat Valenciana and co-financed with ERDF (OP ERDF of Comunitat Valenciana 2014–2020). PS had an FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport [FPU15/00964]. IH has a PFIS-PhD fellowship [FI19/00072]. ASM has a contract funded by the Spanish Foundation Per Amor a l’Art (FPAA)Peer reviewe

On L2 grammar and processing: the case of oblique relative clauses and the Null-Prep phenomenon

This dissertation investigates the acquisition of oblique relative clauses in L2 Spanish by English and Moroccan Arabic speakers in order to understand the role of previous linguistic knowledge and its interaction with Universal Grammar on the one hand, and the relationship between grammatical knowledge and its use in real-time, on the other hand. Three types of tasks were employed: an oral production task, an on-line self-paced grammaticality judgment task, and an on-line self-paced reading comprehension task. Results indicated that the acquisition of oblique relative clauses in Spanish is a problematic area for second language learners of intermediate proficiency in the language, regardless of their native language. In particular, this study has showed that, even when the learners’ native language shares the main properties of the L2, i.e., fronting of the obligatory preposition (Pied-Piping), there is still room for divergence, especially in production and timed grammatical intuitions. On the other hand, reaction time data have shown that L2 learners can and do converge at the level of sentence processing, showing exactly the same real-time effects for oblique relative clauses that native speakers had. Processing results demonstrated that native and non-native speakers alike are able to apply universal processing principles such as the Minimal Chain Principle (De Vincenzi, 1991) even when the L2 learners still have incomplete grammatical representations, a result that contradicts some of the predictions of the Shallow Structure Hypothesis (Clahsen & Felser, 2006). Results further suggest that the L2 processing and comprehension domains may be able to access some type of information that it is not yet available to other grammatical modules, probably because transfer of certain L1 properties occurs asymmetrically across linguistic domains. In addition, this study also explored the Null-Prep phenomenon in L2 Spanish, and proposed that Null-Prep is an interlanguage stage, fully available and accounted within UG, which intermediate L2 as well as first language learners go through in the development of pied-piping oblique relative clauses. It is hypothesized that this intermediate stage is the result of optionality of the obligatory preposition in the derivation, when it is not crucial for the meaning of the sentence, and when the DP is going to be in an A-bar position, so it can get default case. This optionality can be predicted by the Bottleneck Hypothesis (Slabakova, 2009c) if we consider that these prepositions are some sort of functional morphology. This study contributes to the field of SLA and L2 processing in various ways. First, it demonstrates that the grammatical representations may be dissociated from grammatical processing in the sense that L2 learners, unlike native speakers, can present unexpected asymmetries such as a convergent processing but divergent grammatical intuitions or production. This conclusion is only possible under the assumption of a modular language system. Finally, it contributes to the general debate of generative SLA since in argues for a fully UG-constrained interlanguage grammar

On L2 Grammar and Processing: The Case of Oblique Relative Clauses and the Null-Prep Phenomenon

275 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2010.This study contributes to the field of SLA and L2 processing in various ways. First, it demonstrates that the grammatical representations may be dissociated from grammatical processing in the sense that L2 learners, unlike native speakers, can present unexpected asymmetries such as a convergent processing but divergent grammatical intuitions or production. This conclusion is only possible under the assumption of a modular language system. Finally, it contributes to the general debate of generative SLA since in argues for a fully UG-constrained interlanguage grammar.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD