Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by β-secretase or α-secretase, followed by γ-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced β-secretase cleavage, are increased in SOD1^G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1^G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP β-secretase cleavage site, resulted in reduction of mutant SOD1^G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1^G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1^G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPβ and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease.     

The general characteristics of the epidemic process and of the circulating streptococcal strains during an upsurge in scarlatina morbidity in Leningrad

The dynamics of scarlet fever morbidity in Leningrad for many years was studied and the absence of any effect produced by the existing system of preventive measures against this disease for the last 30 years was shown. On the basis of epidemiological and bacteriological data the authors came to the conclusion on the unity of the epidemic process of scarlet fever in the whole city and the relatively autonomous character of the process in individual districts. The necessity of the realization of epidemiological surveillance on streptococcal infection, with special emphasis on the multilevel social structure of the city and the wide use of the bacteriological diagnosis of streptococcal diseases, is substantiated.     

Quantification of NADH:ubiquinone oxidoreductase (complex I) content in biological samples

Impairments in mitochondrial energy metabolism have been implicated in human genetic diseases associated with mitochondrial and nuclear DNA mutations, neurodegenerative and cardiovascular disorders, diabetes, and aging. Alteration in mitochondrial complex I structure and activity has been shown to play a key role in Parkinson''s disease and ischemia/reperfusion tissue injury, but significant difficulty remains in assessing the content of this enzyme complex in a given sample. The present study introduces a new method utilizing native polyacrylamide gel electrophoresis in combination with flavin fluorescence scanning to measure the absolute content of complex I, as well as α-ketoglutarate dehydrogenase complex, in any preparation. We show that complex I content is 19 ± 1 pmol/mg of protein in the brain mitochondria, whereas varies up to 10-fold in different mouse tissues. Together with the measurements of NADH-dependent specific activity, our method also allows accurate determination of complex I catalytic turnover, which was calculated as 10⁴ min⁻¹ for NADH:ubiquinone reductase in mouse brain mitochondrial preparations. α-ketoglutarate dehydrogenase complex content was determined to be 65 ± 5 and 123 ± 9 pmol/mg protein for mouse brain and bovine heart mitochondria, respectively. Our approach can also be extended to cultured cells, and we demonstrated that about 90 × 10³ complex I molecules are present in a single human embryonic kidney 293 cell. The ability to determine complex I content should provide a valuable tool to investigate the enzyme status in samples after in vivo treatment in mutant organisms, cells in culture, or human biopsies.     

Ecological and toxicological control over the status of the environment by the methods of physicochemical biology

Xenobiotic metabolism in the fish liver has been investigated with a view of developing test-system for biomonitoring based on multienzyme membrane-bound complexes. Extraction methods of xenobiotics from harmful pollutants and some biological tissue have been described using various sorbents and solvents. The own and literary data on the study of mutagenic effect of this contaminants and carcinogens in the Ames test-system in the presence of postmitochondrial fraction S9 from fish liver with 3-methylcholanthrene induced by microsomal oxidation system have been demonstrated.     

Chemical modification of an antineoplastic antibiotic bleomycetin by the C-end fragment]

Bleomycetin, an antitumor antibiotic, was subjected to chemical modification by the C-end fragment i.e. the residue of 3-[(4-aminobutyl)amino]propylamine (spermidine++) with acylation, carbamoylation and reducing alkylation, which yielded its new semisynthetic derivatives. The use of physicochemical methods showed that the chemical modification involved the primary and secondary amino groups++ of spermidine++ and gave rise to N,N'-diacyl, N,N'-dicarbamoyl and N,N'-dialkyl bleomycetins. The biological properties of the derivatives, i.e. their cytotoxic activity, acute and pulmonary toxicities were studied. The transformation of bleomycetin by the C-end fragment lowered the antibiotic toxicity and was believed to be a promising approach to modifying its molecule.     

Industrial fisheries have reversed the carbon sequestration by tuna carcasses into emissions

To limit climate warming to 2°C above preindustrial levels, most economic sectors will need a rapid transformation toward a net zero emission of CO₂. Tuna fisheries is a key food production sector that burns fossil fuel to operate but also reduces the deadfall of large-bodied fish so the capacity of this natural carbon pump to deep sea. Yet, the carbon balance of tuna populations, so the net difference between CO₂ emission due to industrial exploitation and CO₂ sequestration by fish deadfall after natural mortality, is still unknown. Here, by considering the dynamics of two main contrasting tuna species (Katsuwonus pelamis and Thunnus obesus) across the Pacific since the 1980s, we show that most tuna populations became CO₂ sources instead of remaining natural sinks. Without considering the supply chain, the main factors associated with this shift are exploitation rate, transshipment intensity, fuel consumption, and climate change. Our study urges for a better global ocean stewardship, by curbing subsidies and limiting transshipment in remote international waters, to quickly rebuild most pelagic fish stocks above their target management reference points and reactivate a neglected carbon pump toward the deep sea as an additional Nature Climate Solution in our portfolio. Even if this potential carbon sequestration by surface unit may appear low compared to that of coastal ecosystems or tropical forests, the ocean covers a vast area and the sinking biomass of dead vertebrates can sequester carbon for around 1000 years in the deep sea. We also highlight the multiple co-benefits and trade-offs from engaging the industrial fisheries sector with carbon neutrality.     

The extracellular epidermal compartment of mammals

The structure and function of the intercorneocyte cement of the corneal layer of epidermis in mammals has been reviewed on the basis of the author's and published data. Two functions of the layer have been considered: a water-tight barrier and a desquamation. Chemical structure of the barrier has been characterized. Comparison of the barrier in water and terrestrial mammals suggest that the peculiarities of the barrier correlate with different pathways of keratinization. Factors that determine the adhesion have been described. The authors show the possibility to use natural models for studying the processes of keratinization and, in particular, functioning the intercellular compartment of the corneal layer.     

Rose scent: genomics approach to discovering novel floral fragrance-related genes

For centuries, rose has been the most important crop in the floriculture industry; its economic importance also lies in the use of its petals as a source of natural fragrances. Here, we used genomics approaches to identify novel scent-related genes, using rose flowers from tetraploid scented and nonscented cultivars. An annotated petal EST database of approximately 2100 unique genes from both cultivars was created, and DNA chips were prepared and used for expression analyses of selected clones. Detailed chemical analysis of volatile composition in the two cultivars, together with the identification of secondary metabolism-related genes whose expression coincides with scent production, led to the discovery of several novel flower scent-related candidate genes. The function of some of these genes, including a germacrene D synthase, was biochemically determined using an Escherichia coli expression system. This work demonstrates the advantages of using the high-throughput approaches of genomics to detail traits of interest expressed in a cultivar-specific manner in nonmodel plants. EST sequences were submitted to the GenBank database (accession numbers BQ 103855 to BQ 106728).