Have labour practices and human rights disclosures enhanced corporate accountability? The case of the GRI framework

This paper critically evaluates Transnational Corporations’ (TNCs) claimed adherence to the Global Reporting Initiative (GRI)´s ‘labour’ and ‘human rights’ reporting guidelines and examines how successful the GRI has been in enhancing comparability and transparency. We found limited evidence of TNCs discharging their accountability to their workforce and, rather, we found evidence to suggest that disclosure was motivated more by enhancing their legitimacy. TNCs failed to adhere to the guidelines, which meant that material information items were often missing, rendering comparability of information meaningless. Instead, TNCs reported large volumes of generic/anecdotal information without acknowledging the impediments they faced in practice

Personalized medicine to improve treatment of dopa-responsive dystonia—a focus on tyrosine hydroxylase deficiency

Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients

The quaternary structure of human tyrosine hydroxylase:effects of dystonia‐associated missense variants on oligomeric state and enzyme activity

Abstract Tyrosine hydroxylase (TH) is a multi‐domain, homo‐oligomeric enzyme that catalyses the rate‐limiting step of catecholamine neurotransmitter biosynthesis. Missense variants of human TH are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA‐responsive dystonia (DRD). We expressed isoform 1 of human TH (hTH1) and its dystonia‐associated missense variants in E. coli, analysed their quaternary structure and thermal stability using size‐exclusion chromatography, circular dichroism, multi‐angle light scattering, transmission electron microscopy, small‐angle X‐ray scattering and assayed hydroxylase activity. Wild‐type (WT) hTH1 was a mixture of enzymatically stable tetramers (85.6%) and octamers (14.4%), with little interconversion between these species. We also observed small amounts of higher order assemblies of long chains of enzyme by transmission electron microscopy. To investigate the role of molecular assemblies in the pathogenesis of DRD, we compared the structure of WT hTH1 with the DRD‐associated variants R410P and D467G that are found in vicinity of the predicted subunit interfaces. In contrast to WT hTH1, R410P and D467G were mixtures of tetrameric and dimeric species. Inspection of the available structures revealed that Arg‐410 and Asp‐467 are important for maintaining the stability and oligomeric structure of TH. Disruption of the normal quaternary enzyme structure by missense variants is a new molecular mechanism that may explain the loss of TH enzymatic activity in DRD. Unstable missense variants could be targets for pharmacological intervention in DRD, aimed to re‐establish the normal oligomeric state of TH