Hybrid Powertrain Technology Assessment through an Integrated Simulation Approach

Global automotive fuel economy and emissions pressures mean that 48 V hybridisation will become a significant presence in the passenger car market. The complexity of powertrain solutions is increasing in order to further improve fuel economy for hybrid vehicles and maintain robust emissions performance. However, this results in complex interactions between technologies which are difficult to identify through traditional development approaches, resulting in sub-optimal solutions for either vehicle attributes or cost. The results presented in this paper are from a simulation programme focussed on the optimisation of various advanced powertrain technologies on 48 V hybrid vehicle platforms. The technologies assessed include an electrically heated catalyst, an insulated turbocharger, an electric water pump and a thermal management module. The novel simulation approach undertaken uses an integrated toolchain capturing thermal, electrical and mechanical energy usage across all powertrain sub-systems. Through integrating 0-D and 1-D sub-models into a single modelling environment, the operating strategy of the technologies can be optimised while capturing the synergies that exist between them. This approach enables improved and more informed cost/benefit ratios for the technologies to be produced and better attributes by identifying the optimum strategy for the vehicle. The results show the potential for CO2 reductions in the range of 2-5% at no additional cost, through co-optimisation of the technologies in a single simulation environment. The simulation work forms part of the THOMSON project, a collaborative research project aiming to develop cost effective 48 V solutions, in order to reduce the environmental impact of the transportation sector.</p

Hybrid Powertrain Technology Assessment through an Integrated Simulation Approach

Global automotive fuel economy and emissions pressures mean that 48 V hybridisation will become a significant presence in the passenger car market. The complexity of powertrain solutions is increasing in order to further improve fuel economy for hybrid vehicles and maintain robust emissions performance. However, this results in complex interactions between technologies which are difficult to identify through traditional development approaches, resulting in sub-optimal solutions for either vehicle attributes or cost. The results presented in this paper are from a simulation programme focussed on the optimisation of various advanced powertrain technologies on 48 V hybrid vehicle platforms. The technologies assessed include an electrically heated catalyst, an insulated turbocharger, an electric water pump and a thermal management module. The novel simulation approach undertaken uses an integrated toolchain capturing thermal, electrical and mechanical energy usage across all powertrain sub-systems. Through integrating 0-D and 1-D sub-models into a single modelling environment, the operating strategy of the technologies can be optimised while capturing the synergies that exist between them. This approach enables improved and more informed cost/benefit ratios for the technologies to be produced and better attributes by identifying the optimum strategy for the vehicle. The results show the potential for CO2 reductions in the range of 2-5% at no additional cost, through co-optimisation of the technologies in a single simulation environment. The simulation work forms part of the THOMSON project, a collaborative research project aiming to develop cost effective 48 V solutions, in order to reduce the environmental impact of the transportation sector.</p

FAM222B Is Not a Likely Novel Candidate Gene for Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are prevalent slow-flow vascular lesions which harbour the risk to develop intracranial haemorrhages, focal neurological deficits, and epileptic seizures. Autosomal dominantly inherited CCMs were found to be associated with heterozygous inactivating mutations in 3 genes, CCM1(KRIT1), CCM2(MGC4607), and CCM3(PDCD10) in 1999, 2003 and 2005, respectively. Despite the availability of high-throughput sequencing techniques, no further CCM gene has been published since. Here, we report on the identification of an autosomal dominantly inherited frameshift mutation in a gene of thus far unknown function, FAM222B(C17orf63), through exome sequencing of CCM patients mutation-negative for CCM1-3. A yeast 2-hybrid screen revealed interactions of FAM222B with the tubulin cytoskeleton and STAMBP which is known to be associated with microcephaly-capillary malformation syndrome. However, a phenotype similar to existing models was not found, neither in fam222bb/fam222ba double mutant zebrafish generated by transcription activator-like effector nucleases nor in an in vitro sprouting assay using human umbilical vein endothelial cells transfected with siRNA against FAM222B. These observations led to the assumption that aberrant FAM222B is not involved in the formation of CCMs

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.Peer reviewedFinal Accepted Versio

Mutations In The Interleukin Receptor Il11Ra Cause Autosomal Recessive Crouzon-Like Craniosynostosis

We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis.PubMedScopu