Resensitization of HTLV-1 infected T cells towards apoptosis by rocaglamide involves inhibition of protein translation

Human T cell Leukemia Virus Type 1 (HTLV-1) is a retrovirus, associated with several diseases including Adult T-cell Leukemia/Lymphoma (ATL). Because of apoptosis resistance treatment provides only limited benefits for ATL. CD95/CD95L-mediated apoptosis is an important mechanism of T cell homeostasis. We have previously shown that HTLV-1 infected T cells are more resistant to CD95L-induced apoptosis as compared to non HTLV-1 infected T cells. In this study we showed that HTLV-1 infected T cells are also resistant towards TRAIL, which suggests a general mechanism of resistance towards death receptor-mediated apoptosis. The basis of apoptotic resistance in HTLV-1 infected T cells was suggested to be due to the elevated expression of several anti-apoptotic proteins involved in modulation of the intrinsic cell death pathway. Recently our group further found that apoptosis is also blocked within the extrinsic cell death pathway by high c-FLIP expression. C-FLIP is an anti-apoptotic protein that blocks death receptor-mediated apoptosis at the DISC level. To overcome resistance, we have treated HTLV-1 infected T cells with CD95L or TRAIL in combination with an herbal compound, Rocaglamide, derived from a Traditional Chinese Medicinal plant (TCM). We showed that one of the Rocaglamide derivatives tested, Roc-AR, sensitizes HTLV-1 infected T cells towards CD95L- and TRAIL-mediated apoptosis via down-regulation of c-FLIP expression at the translational level. Further investigation of the molecular mechanisms by which Roc-AR suppresses c-FLIP translation, revealed a mechanism different from other known translation inhibitors. Roc-AR strongly inhibits the Ras pathway leading to the inhibition of Mnk-1, a protein kinase essential for the activation of the translation initiation factor 4E (eIF4E). Thus, blocking activation of eIF4E by Roc-AR leads to inhibition of cap-dependent eukaryotic translation at the initiation stage. Most importantly, Roc-AR does not sensitize normal peripheral blood T cells to CD95L-and TRAIL-induced apoptosis. Our study raises the possibility to develop Roc-AR as CD95L or TRAIL adjuvant for treatment of ATL and other types of T-cell tumors

Возможностим развития конкуренции на рынках теплоснабжения Донбасса

Проаналізовано стан ситем теплопостачання Донбасу, виявлено зниження виробництва та відпуску теплової енергії, що викликано появою конкурента — автономного опалення. Обгрунтовано причини протиріччя законодавства, що регулює діяльність у сфері комунального теплопостачання — природної монополії, в результаті чого порушені конституційні, цивільні, споживчі права людей. Розглянуто практику регулювання ринків теплопостачання в країнах з розвиненою ринковою економікою, і можливості застосування їх досвіду в Україні. Визначено роль держави, як найважливішого регулятора, який здійснює контроль за ринком теплопостачання, і є влавником стратегічно важливих підприємств сектора. Ключові слова: централізоване теплопостачання, природна монополія, автономне опалення, конкуренція, приватний капітал, державне регулювання.Проанализировано состояние ситем теплоснабжения Донбасса, выявлено снижение производства и отпуска тепловой энергии, что вызвано появлением конкурента — автономного отопления. Обоснованы причины протеворечивости законодательства регулирующего деятельность в сфере коммунального теплоснабжения — естественной монополии, в результате чего нарушены конституционные, гражданские, потребительские права людей. Рассмотрена практика регулирования рынков теплоснабжения в странах с развитой рыночной экономикой, и возможности применения их опыта в Украине. Определена роль государства, как важнейшего регулятора, осуществляющего контроль за рынком теплоснабжения, и собственика стратегически важных предприятий сектора. Ключевые слова: централизованное теплоснабжение, естественная монополия, автономное отопление, конкуренция, частный капитал, государственное регулирование.The state of Donbass Heating System Works, showed a reduction in production and supply of heat energy that is caused by the emergence of competitors — independent heating. Substantiated reasons imperfect legislation governing activities in the field of district heating — natural monopoly, resulting in a violation of the constitutional, civil, consumer rights of people. The practical management of district heating markets in countries with developed market economies, and the possibility of applying their experience in Ukraine. Defined the place of government as an important regulator, controlling the heating market, and the owners of strategically important enterprises in the sector. Key words: district heating, natural monopoly, independent heating, competition, private capital, government regulation

Bacteroides fragilis fucosidases facilitate growth and invasion of Campylobacter jejuni in the presence of mucins

The enteropathogenic bacterium Campylobacter jejuni was considered to be non-saccharolytic, but recently it emerged that l-fucose plays a central role in C. jejuni virulence. Half of C. jejuni clinical isolates possess an operon for l-fucose utilization. In the intestinal tract, l-fucose is abundantly available in mucin O-linked glycan structures, but C. jejuni lacks a fucosidase enzyme essential to release the l-fucose. We set out to determine how C. jejuni can gain access to these intestinal l-fucosides. Growth of the fuc + C. jejuni strains 129,108 and NCTC 11168 increased in the presence of l-fucose while fucose permease knockout strains did not benefit from additional l-fucose. With fucosidase assays and an activity-based probe we confirmed that Bacteriodes fragilis, an abundant member of the intestinal microbiota, secretes active fucosidases. In the presence of mucins, C. jejuni was dependent on B. fragilis fucosidase activity for increased growth. C. jejuni invaded Caco-2 intestinal cells that express complex O-linked glycan structures that contain l-fucose. In infection experiments, C. jejuni was more invasive in the presence of B. fragilis and this increase is due to fucosidase activity. We conclude that C. jejuni fuc + strains are dependent on exogenous fucosidases for increased growth and invasion. This article is protected by copyright. All rights reserved