| 1. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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| 2. |
- Dhanabalachandran, Kaviya, et al.
(författare)
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A balancing act : Ordering algorithm and image-schematic action descriptors for stacking objects by household robots
- 2022
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Ingår i: Proceedings of the Joint Ontology Workshops 2022, Episode VIII: The Svear Sommar of Ontology. - : CEUR-WS.
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Konferensbidrag (refereegranskat)abstract
- Optimising object order in stacking problems remains a hard problem for cognitive robotics research. In this paper, we continue our work on using the spatiotemporal relationships called image schemas to represent affordance spaces founded on object properties. Based on object properties, we introduce a stacking-order algorithm and describe the action descriptors using an image-schematic event segmentation format by describing a small subset using the Image Schema Logic ISL???.
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| 3. |
- Dhanabalachandran, Kaviya, et al.
(författare)
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Cutting Events : Towards Autonomous Plan Adaption by Robotic Agents through Image-Schematic Event Segmentation
- 2021
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Ingår i: Proceedings of the 11th on Knowledge Capture Conference. - New York, NY, USA : ACM Digital Library. - 9781450384575 ; , s. 25-32
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Konferensbidrag (refereegranskat)abstract
- Autonomous robots struggle with plan adaption in uncertain and changing environments. Although modern robots can make popcorn and pancakes, they are incapable of performing such tasks in unknown settings and unable to adapt action plans if ingredients or tools are missing. Humans are continuously aware of their surroundings. For robotic agents, real-time state updating is time-consuming and other methods for failure handling are required. Taking inspiration from human cognition, we propose a plan adaption method based on event segmentation of the image-schematic states of subtasks within action descriptors. For this, we reuse action plans of the robotic architecture CRAM and ontologically model the involved objects and image-schematic states of the action descriptor cutting. Our evaluation uses a robot simulation of the task of cutting bread and demonstrates that the system can reason about possible solutions to unexpected failures regarding tool use.
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| 4. |
- Dhanabalachandran, Kaviya, et al.
(författare)
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Getting on top of things : Towards intelligent robotic object stacking through image-schematic reasoning
- 2022
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Ingår i: Proceedings of the Sixth Image Schema Day 2022. - : CEUR-WS.
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Konferensbidrag (refereegranskat)abstract
- In this extended abstract, we present initial work on intelligent object stacking by household robots using a symbolic approach grounded in image schema research. Image schemas represent spatiotemporal relationships that capture objects’ affordances and dispositions. Therefore, they offer the first step to ground semantic information in symbolic descriptions. We hypothesise that for a robot to successfully stack objects of different dispositions, these relationships can be used to more intelligently identify both task constraints and relevant event segments.
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| 5. |
- Ebrahimi-Fakhari, Darius, et al.
(författare)
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
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Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Tidskriftsartikel (refereegranskat)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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