Identifying Extreme Risks in Critical Infrastructure Interdependencies

Abstract: Critical infrastructures like our power generation facilities and water supply form highly interconnected networks that are mutually dependent and any failure can cascade through the network, resulting in devastating impact on health, safety and the economy. These catastrophic events/disruptions can be triggered by environmental accidents, geological/weather phenomena, disease pandemics, etc. The disruptions can be caused/exacerbated by their being unexpected, but they may actually be expected if relevant data have been accounted for. To help account for and thereby anticipate such disruptions, one way is to identify potential unforeseen interdependencies among infrastructure components that can lead to extreme disruptions upon some failure in the network. This paper shows how a simulation model for cascading failures and a risk analysis/optimization approach can be applied to search for unforeseen interdependencies and failure points that give rise to the highest risk in a network. Citation: Tai, K., Kizhakkedath, A., Lin, J., Tiong, R.L.K. & Sim, M.S. (2014). Identifying Extreme Risks in Critical Infrastructure Interdependencies. In: Campbell P. and Perez P. (Eds), Proceedings of the International Symposium of Next Generation Infrastructure, 1-4 October 2013, SMART Infrastructure Facility, University of Wollongong, Australia

Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome

Abstract Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing

A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement

Abstract Background The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. Results We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) in ELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5′ end unprocessed mt-RNAs compared to the control fibroblast cells. Conclusions The only three previously reported families with defects in ELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum of ELAC2- associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes

A Perspective on the Commercial Viability of Perovskite Solar Cells

Perovskite solar cells (PSCs) have received a large amount of research funds due to their potential as a frontrunner in a new generation of solar cells; consequently, the desire to commercialize this technology is mounting. In this roadmap, the knowledge and the technological gaps between laboratory and industry are critically analyzed from the perspective of 5S criteria (Stability, Safety, Sustainability, Scalability, and Storage). To avoid any favoritism in the arguments toward commercializing this technology, herein, the average parameters of PSCs (photoconversion efficiency, durability, cost, manufacturability, and sustainability) estimated from previous studies are analyzed and discussed. Unique opportunities for PSCs in their current stage of achievements are identified, where application-driven, instead of performance-driven, developments are shown to favor their commercialization. Efforts required to improve the average performance of PSCs to state-of-the-art levels are also identified and discussed

A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking

BACKGROUND: The rare autosomal genetic disorder, Spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL), is reported to be caused by missense or splice site mutations in the human discoidin domain receptor 2 (DDR2) gene. Previously our group has established that trafficking defects and loss of ligand binding are the underlying cellular mechanisms of several SMED-SL causing mutations. Here we report the clinical characteristics of two siblings of consanguineous marriage with suspected SMED-SL and identification of a novel disease-causing mutation in the DDR2 gene. METHODS: Clinical evaluation and radiography were performed to evaluate the patients. All the coding exons and splice sites of the DDR2 gene were sequenced by Sanger sequencing. Subcellular localization of the mutated DDR2 protein was determined by confocal microscopy, deglycosylation assay and Western blotting. DDR2 activity was measured by collagen activation and Western analysis. RESULTS: In addition to the typical features of SMED-SL, one of the patients has an eye phenotype including visual impairment due to optic atrophy. DNA sequencing revealed a novel homozygous dinucleotide deletion mutation (c.2468_2469delCT) on exon 18 of the DDR2 gene in both patients. The mutation resulted in a frameshift leading to an amino acid change at position S823 and a predicted premature termination of translation (p.S823Cfs*2). Subcellular localization of the mutant protein was analyzed in mammalian cell lines, and it was found to be largely retained in the endoplasmic reticulum (ER), which was further supported by its N-glycosylation profile. In keeping with its cellular mis-localization, the mutant protein was found to be deficient in collagen-induced receptor activation, suggesting protein trafficking defects as the major cellular mechanism underlying the loss of DDR2 function in our patients. CONCLUSIONS: Our results indicate that the novel mutation results in defective trafficking of the DDR2 protein leading to loss of function and disease. This confirms our previous findings that DDR2 missense mutations occurring at the kinase domain result in retention of the mutant protein in the ER