Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.Diseases caused by insect-borne trypanosomatid parasites are a significant and neglected public health problem worldwide. Chagas' disease, caused by infection with Trypanosoma cruzi, is a major agent of disease in Latin America, with 16 to 18 million infected individuals and an annual death toll of 50,000. It is also an emerging problem in the United States, where an estimated 100,000 infected individuals reside (16). Trypanosoma brucei subspp., the causative agents of human African trypanosomiasis or "sleeping sickness," infect 50,000 annually. Approximately 300,000 to 500,000 people have trypanosomiasis and will die if not treated (18). Current therapeutic options for Trypanosoma infections, benznidazole and nifurtimox for Chagas' disease treatment and suramin, pentamidine, melarsoprol, and eflornithine for treatment of sleeping sickness, are far from ideal (8,17). These drugs all suffer from one or more disadvantages-high cost, parenteral administration, long treatment courses (months), high clinical failure rates, or parasite drug resistance-and they elicit multiple, serious, and potentially fatal toxic side effects. New therapeutic alternatives are obviously desirable for treatment of these lifethreatening infections.Artemisinin is a sesquiterpene lactone isolated from Artemisia annua, an annual herb that has been used in traditional Chinese medicine for over 2,000 years (21). Artemisinin is hydrophobic, passes biological membranes easily, and is a potent antimalarial with effective 50% inhibitory concentrations (IC 50 values) ranging from 4.2 to 16.2 nM for different derivatives. Oral, parenteral, or rectal dosages achieve micromolar plasma concentrations (22). Artemisinin derivatives have been used to treat malaria cases around the world, and their extensive usage has not been associated with any significant toxicity (19). Artemisinin generates bioreactive radicals capable of intracellular damage, depolarizes mitochondrial membrane potential in yeast, and inhibits the Plasmodium falciparum endoplasmic reticulum calcium pump (SERCA), and artemisininresistant P. falciparum contains SERCA mutations (9,13,14,(20)(21)(22).Artemisinin compounds also show efficacy against Leishmania spp. of trypanosomatid parasites, achieving 50% killing at 750 nM for Leishmania major promastigotes, at 3 to 30 M for intracellular amastigote stages in macrophages, and at 1.4 to 382.9 M against Leishmania infantum promastigotes (1, 23). Artemether treatment (50 mg/kg of body weight/day) of footpad lesions in mice, by oral, intralesional, intramuscular, or intravenous administration, significantly reduces lesion size and L. major parasite numbers (23). Oral dih...
BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1) to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34) and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1). Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII) carboxy terminal domain (P-CTD), phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1 mutant breast cells. These results extend the mechanistic links between BRCA1 and transcriptional consequences in response to DNA damage and suggest an important role for RNAPII P-CTD cleavage in BRCA1-mediated cancer suppression.
Аннотация. В статье рассматриваются особенности нормативно-правового регулирования деятельности по перевозке пассажиров и багажа легковым такси в Российской Федерации в контексте обеспечения безопас ности дорожного движения. Анализируется специфика участия в дорожном движении транспортных средств, предназначенных для перевозки пассажиров в качестве легкового такси. Обращается внимание на формальность существующих требований, предъявляемых к водителям, претендующим на получение разрешения на осуществление указанного вида деятельности, и обосновывается необходимость их корректировки. Вносятся предложения, направленные на совершенствование законодательства в сфере таксомоторных перевозок. Исследуются отдельные коллизии, возникающие в правоприменительной практике сотрудников Госавтоинспекции при реализации контрольно-надзорных полномочий за соблюдением легковыми такси требований по обеспечению безопасности дорожного движения, и предлагаются пути их возможного разрешения. Ключевые слова: такси, безопасность дорожного движения, пассажирские перевозки, цветографическая схема, водитель. Separate Aspects of Administrative and Legal Regulation of Activity of Passenger Taxis * Преподаватель кафедры специальной подготовки Орловского юридического института МВД России имени В. В. Лукьянова. ** Lecturer of the Department of Special Training at Lukyanov Orel Law Institute of the Ministry of the Interior of Russia. 1 Состояние таксомоторной отрасли в России с точки зрения безопасности дорожного движения : исследование аналит. центра при Правительстве Рос.
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