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Background: Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important because liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. Objective: The aim of the study was to determine the incidence of MLD in children younger than 2 years with ALF and the utility of routine investigations to detect MLD. Methods: Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009 to 2011. All were extensively investigated using an established protocol. Genes implicated in mitochondrial DNA depletion syndrome were sequenced in all cases and tissue mtDNA copy number measured where available. Results: Five infants (17%) had genetically proven MLD: DGUOK (n = 2), POLG (n = 2), and MPV17 (1). Four of these died, whereas 1 recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA copy number but pathogenic mutations were not detected. One of these developed fatal multisystemic disease after LT, whereas 5 who survived remain well without evidence of multisystemic disease up to 6 years later. Magnetic resonance spectroscopy did not distinguish between those with and without MLD. Conclusions: Low liver mtDNA copy number may be a secondary phenomenon in ALF. Screening for mtDNA maintenance gene mutations may be the most efficient way to confirm MLD in ALF in the first 2 years of life.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

Maternally-inherited mitochondrial DNA (mtDNA) mutations cause symptoms of Leber’s hereditary optic neuropathy (LHON) in~ 1 in 30,000 individuals. Most of the affected individuals lack respiratory chain defects and there is no proven prophylactic treatment. We identified two families (Figure 1A) and one singleton case (Appendix e-1) harbouring the m.13051G>A pathogenic mtDNA mutation. This mutation was homoplasmic (Figure e-1) but no respiratory chain defect was apparent in skeletal muscle (Figure e-2, Table e-1). Three children were severely affected with lactic acidosis, two with Leigh syndrome (Patient 1 and 2; Figure 1B) and one with a Leigh-like phenotype (Patient 5). Previous authors have shown that mtDNA and mitochondrial mass are increased in individuals harbouring LHON mutations. They suggested that an up-regulation of mitochondrial biogenesis is protective, as the highest mitochondrial content was found in symptom-free carriers. We believe this increase in biogenesis reflects heightened mitochondrial turnover and therefore investigated mitophagy, a cellular mechanism whereby redundant or dysfunctional mitochondria are recycled.

Kidney dysfunction is being increasingly associated with mitochondrial diseases and coenzyme Q(10) (CoQ) deficiency. The assessment of CoQ status requires the biochemical determination of CoQ in biological fluids and different cell types, but no methods have been developed as yet for the analysis of CoQ in excretory systems. The aim of this study was to standardize a new procedure for urinary CoQ determination and to establish reference values for a paediatric population. Urinary CoQ was analyzed by HPLC with electrochemical detection. Reference values (n=43) were stratified into two age groups (2-10 years: range 24-109 nmol CoQ/gram of pellet protein; 11-17 years: range 43-139 nmol CoQ/gram of pellet protein). In conclusion, urinary CoQ analysis is a noninvasive, reliable, and reproducible method to determine urinary tract CoQ status. (c) 2015 BioFactors, 41(6):424-430, 2015

Text and data mining (TDM) is an important technique for analysing and extracting new insights and knowledge from the exponentially increasing store of digital data (‘Big Data’). TDM is useful to researchers of all kinds, from historians to medical experts, and its methods are relevant to organisations throughout the public and private sectors. TDM represents a significant economic opportunity for Europe. Prolific use of TDM would add tens of billions of Euros in value to the EU’s aggregate GDP. At present, the use of TDM tools by researchers in Europe appears to be lower than in its main competitors. There is a serious risk that Europe’s relative competitive position as a research location for the exploitation of digital data will deteriorate further, if steps are not taken to address the issues discussed in this report.

Everyone agrees that copyright in the European Union is in a state of crisis. But there is disagreement on what caused it and what to do about it. Rights holders generally complain that copyright law has left them defenceless against mass-scale infringement over digital networks, and call for enhanced copyright enforcement mechanisms. Authors lament that the law does little to protect their right to receive fair compensation from the copyright industries and the users of their works alike. Users and consumers accuse the copyright industries of abusing copyright, and using it as an instrument to conserve monopoly power and sustain outdated business models.

The architectural concept of the John Hope Gateway is that of a floating timber canopy over the entrance to the Royal Botanic Garden, Edinburgh. This paper presents the Engineering challenges encountered and the bespoke solutions that were generated, which include a diagrid of tapering glulam beams at roof level and the use of cross-laminated timber floors and walls. Slim cruciform steel columns are used to emphasise the elegance of the supported timber structure. The building is on two storeys with an overall dimension of approximately 100 metres × 50 metres. Spans between columns vary between 8 and 6 metres. It uses 2750 square metres of cross-laminated timber slabs, 226mm thick on the first floor and 146mm at roof level. Although timber is becoming used more and more regularly for structures in Scotland, this building is not only very high profile, but also it is also structurally demanding. Amongst the issues discussed in the paper are: Connection details at the tops of the column heads, where the roof is carried on thin steel rods; the manufacturing challenges relating to tolerances in fabrication and erection; the use of large areas of exposed cross-laminated timber in a building with public access; fire resistance and the use of timber in an external environment.