The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.     

Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan

Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.     

The mathematician Rehuel Lobatto advocates life insurances in The Netherlands in the period 1830–1860

In 1807 the first life insurance society was established in The Netherlands. In the second half of the century, life insurance societies underwent considerable expansion. During the intervening period, the lines had to be laid along which this new phenomenon was to develop in the future: between 1827 and 1830, the government started discussing the nature of its responsibility in this field and the kind of policy to be developed, and in 1830, a book on the organization of life insurance societies, the calculation of life annuities and widows' fund premiums was published, written by the mathematician Rehuel Lobatto. This book played an important role in the government's discussion. Royal Decrees which prescribed government approval for the establishment of life assurance societies were promulgated in 1830, 1833 and 1840. In 1832, Lobatto became the government's scientific adviser on the assessment of the calculations performed by these societies, and in the same year, he was also appointed adviser to the first life insurance society. From 1832 until his death in 1866 he advised the company on the use of life tables for life as well as for reversionary annuities, and he calculated the premiums based on these life tables. Another decree was promulgated in 1864 prescribing exactly which life tables were to be used. Because Lobatto probably played a part in this decree, he was responsible for a very ‘conservative’ government policy, which was no longer adequate in the second half of the century.     

Marcelin Berthelot's first publication in 1850, on the subjection of liquids to tension

The famous French chemist, Marcelin Berthelot, published his first scientific paper in 1850. However, reference to this paper has been largely ignored in the various accounts of his lasting contributions to chemistry. The probable reason for this is that this paper is concerned with a method of subjecting a liquid to tension, and it is more appropriate to regard it as a paper on physics rather than on chemistry. In the work described in this largely-forgotten paper, written whilst he was still a young research student, Berthelot showed that liquids contained in his ‘Berthelot tube’ could withstand a considerable tension; and he is the first person to have observed cavitation, a phenomenon which has been studied so widely this century. The next mention in the literature of the Berthelot tube method is at the turn of the present century, after which it again seems to have been forgotten until the 1940s; since then there has been considerable progress using the Berthelot tube technique. In this paper the work described in Berthelot's original paper is discussed in some detail, and the subsequent fruitful development of the method is also traced and assessed.