52 research outputs found
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy
Voltage-gated calcium (CaV) channels form three sub-families (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVÎČ and α2ÎŽ subunits. The α2ÎŽ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2ÎŽ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy (DEE). Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2ÎŽ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly likely representing a null allele, and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2ÎŽ-1 as a calcium channel subunit, with strongly reduced trafficking of α2ÎŽ-1G209D to the cell surface, and a complete inability of α2ÎŽ-1G209D to increase the trafficking and function of CaV2 channels. Thus biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2ÎŽ-1 and other α2ÎŽ proteins for normal human neuronal development
Highly Tissue Specific Expression of Sphinx Supports Its Male Courtship Related Role in Drosophila melanogaster
Sphinx is a lineage-specific non-coding RNA gene involved in regulating courtship behavior in Drosophila melanogaster. The 5âČ flanking region of the gene is conserved across Drosophila species, with the proximal 300 bp being conserved out to D. virilis and a further 600 bp region being conserved amongst the melanogaster subgroup (D. melanogaster, D. simulans, D. sechellia, D. yakuba, and D. erecta). Using a green fluorescence protein transformation system, we demonstrated that a 253 bp region of the highly conserved segment was sufficient to drive sphinx expression in male accessory gland. GFP signals were also observed in brain, wing hairs and leg bristles. An additional âŒ800 bp upstream region was able to enhance expression specifically in proboscis, suggesting the existence of enhancer elements. Using anti-GFP staining, we identified putative sphinx expression signal in the brain antennal lobe and inner antennocerebral tract, suggesting that sphinx might be involved in olfactory neuron mediated regulation of male courtship behavior. Whole genome expression profiling of the sphinx knockout mutation identified significant up-regulated gene categories related to accessory gland protein function and odor perception, suggesting sphinx might be a negative regulator of its target genes
Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome
Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patientsâ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways
LATERAL LOAD RESISTANCE OF PARALLEL BAMBOO STRAND PANEL-TO-METAL SINGLE-BOLT CONNECTIONS â PART I: YIELD MODEL
The lateral load resistance behavior of single-shear unconstrained metal-to-parellel bamboo strand panel (PBSP) single-bolt connections was investigated. The connection consisted of a PSBP main member fastened to a metal plate as a side member using a 6-mm diameter bolt without a nut or washer used.  The mechanics-based approach waas used to evaluate critical factors on the lateral load resistance performance of metal-to-PBSP single-bolt connections. Experimental results indicated that the lateral resistance loads of the metal-to-PBSP single-botl connections were significantly affected by its shear strength parallel to bamboo strand orientation, tensile strength perpendicular to bamboo strand orientation and bolt-bearing strenth in PBSPs.  Lower tensile strength perpendicular to bamboo strand orientation of PBSPs can limit its usage as connection members resisting lateral loads. The proposed mechanical model was verified experimentally as a valid means for deriving estimation equations of lateral resistance loads of unconstrained metal-to-PBSP single-bolt connections evaluated in this study.
Recommended from our members
Highly Tissue Specific Expression of <i>Sphinx</i> Supports Its Male Courtship Related Role in <i>Drosophila melanogaster</i>
Sphinx is a lineage-specific non-coding RNA gene involved in regulating courtship behavior in Drosophila melanogaster. The 5âČ flanking region of the gene is conserved across Drosophila species, with the proximal 300 bp being conserved out to D. virilis and a further 600 bp region being conserved amongst the melanogaster subgroup (D. melanogaster, D. simulans, D. sechellia, D. yakuba, and D. erecta). Using a green fluorescence protein transformation system, we demonstrated that a 253 bp region of the highly conserved segment was sufficient to drive sphinx expression in male accessory gland. GFP signals were also observed in brain, wing hairs and leg bristles. An additional âŒ800 bp upstream region was able to enhance expression specifically in proboscis, suggesting the existence of enhancer elements. Using anti-GFP staining, we identified putative sphinx expression signal in the brain antennal lobe and inner antennocerebral tract, suggesting that sphinx might be involved in olfactory neuron mediated regulation of male courtship behavior. Whole genome expression profiling of the sphinx knockout mutation identified significant up-regulated gene categories related to accessory gland protein function and odor perception, suggesting sphinx might be a negative regulator of its target genes.</p
P668: PMP22 single exon deletion in a proband with hematologic malignancy and family history of Charcot-Marie-Tooth disease
Artificial Cathode-Electrolyte Interphase towards High-Performance Lithium-Ion Batteries: A Case Study of ÎČ-AgVO3
Silver vanadates (SVOs) have been widely investigated as cathode materials for high-performance lithium-ion batteries (LIBs). However, similar to most vanadium-based materials, SVOs suffer from structural collapse/amorphization and vanadium dissolution from the electrode into the electrolyte during the Li insertion and extraction process, causing poor electrochemical performance in LIBs. We employ ultrathin AlâOâ coatings to modify ÎČ-AgVOâ (as a typical example of SVOs) by an atomic layer deposition (ALD) technique. The galvanostatic charge-discharge test reveals that ALD AlâOâ coatings with different thicknesses greatly affected the cycling performance. Especially, the ÎČ-AgVOâ electrode with ~10 nm AlâOâ coating (100 ALD cycles) exhibits a high specific capacity of 271 mAh gâ»Âč, and capacity retention is 31%, much higher than the uncoated one of 10% after 100 cycles. The Coulombic efficiency is improved from 89.8% for the pristine ÎČ-AgVOâ to 98.2% for AlâOâ-coated one. Postcycling analysis by cyclic voltammetry (CV), cyclic voltammetry (EIS), and scanning electron microscopy (SEM) disclose that 10-nm AlâOâ coating greatly reduces cathode-electrolyte interphase (CEI) resistance and the charge transfer resistance in the ÎČ-AgVOâ electrode. AlâOâ coating by the ALD method is a promising technique to construct artificial CEI and stabilize the structure of SVOs, providing new insights for vanadium-based electrodes and their energy storage devices.Applied Science, Faculty ofNon UBCEngineering, School of (Okanagan)ReviewedFacult
P297: More than an extra chromosome: Unexpected multiple diagnoses in individuals with Down syndrome
P050: Biallelic variants in POLG2 provides a rare molecular diagnosis in a patient with epilepsy and liver failure
- âŠ