Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate.

Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector

Peasant settlers and the ‘civilizing mission’ in Russian Turkestan, 1865-1917

This article provides an introduction to one of the lesser-known examples of European settler colonialism, the settlement of European (mainly Russian and Ukrainian) peasants in Southern Central Asia (Turkestan) in the late nineteenth and early twentieth centuries. It establishes the legal background and demographic impact of peasant settlement, and the role played by the state in organising and encouraging it. It explores official attitudes towards the settlers (which were often very negative), and their relations with the local Kazakh and Kyrgyz population. The article adopts a comparative framework, looking at Turkestan alongside Algeria and Southern Africa, and seeking to establish whether paradigms developed in the study of other settler societies (such as the ‘poor white’) are of any relevance in understanding Slavic peasant settlement in Turkestan. It concludes that there are many close parallels with European settlement in other regions with large indigenous populations, but that racial ideology played a much less important role in the Russian case compared to religious divisions and fears of cultural backsliding. This did not prevent relations between settlers and the ‘native’ population deteriorating markedly in the years before the First World War, resulting in large-scale rebellion in 1916

Morphofunctional characteristics of hepatocytes after exposure to intermittent normobaric hypoxia in normotensive and hypertensive rats

There are only few studies in which the effect of intermittent normobaric hypoxia on the liver status in animals and people with arterial hypertension has been investigated. That’s why it’s necessary to carry out these studies in animals with high blood pressure. The purpose of this work was to carry out comparative studies of the effect of dosed intermittent normobaric hypoxia on the morphofunctional state of hepatocytes of normotensive (line Wistar) and spontaneously hypertensive (line SHR) rats, age 4 months. The experimental rats were daily exposed to hypoxic gas mixture (12% oxygen in nitrogen) in intermittent mode: 15 minutes deoxygenation / 15 minutes reoxygenation for 2 hours. The duration of the experiment was 28 days. Histological, morphometric and biochemical research methods were used. The histological preparations were made by the standard methods. The slides were photographed using a digital camera on the microscope "Nikon" (Japan). The morphometric analysis was performed on digital images using the computer program "Image J". The activity of cytochrome oxidase and succinate dehydrogenase enzymes in a suspension of hepatocytes mitochondria was determined by the method of R. S. Krivchenkov. An increase was observed in the size of hepatocytes and their nucleus, in the number of binuclear hepatocytes and nucleolus in the liver of both experimental lines of animals after exposure to intermittent normobaric hypoxia. The distance between adjacent nuclei of hepatocytes decreased. Cytochrome oxidase activity in a suspension of mitochondria increased. These morphological changes took place in the liver parenchyma of the both experimental lines of rats. But they were more pronounced in the liver of rats of the Wistar line than in the SHR line. Our data indicated that dosed normobaric hypoxia had a one-way, stimulating effect on the morphofunctional activity of hepatocytes, but the severity of this effect in rats of different lines was not the same. The obtained data can have not only theoretical value, but also be of some practical interest when using intermittent normobaric hypoxia for medical and health purposes in patients with impaired liver function and arterial hypertension