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991.
Tamara Martínez Natalia Wright Marta López-Fraga Ana Isabel Jiménez Covadonga Pañeda 《Human genetics》2013,132(5):481-493
RNA interference is an endogenous mechanism present in most eukaryotic cells that enables degradation of specific mRNAs. Pharmacological exploitation of this mechanism for therapeutic purposes attracted a whole amount of attention in its initial years, but was later hampered due to difficulties in delivery of the pharmacological agents to the appropriate organ or tissue. Advances in recent years have to a certain level started to address this specific issue. Genetic diseases are caused by aberrations in gene sequences or structure; these particular abnormalities are in theory easily addressable by RNAi therapeutics. Sequencing of the human genome has largely contributed to the identification of alterations responsible for genetic conditions, thus facilitating the design of compounds that can address these diseases. This review addresses the currently on-going programs with the aim of developing RNAi and other antisense compounds for the treatment of genetic conditions and the pros and cons that these products may encounter along the way. The authors have focused on those programs that have reached clinical trials or are very close to do so. 相似文献
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The anoxia-dependent elevation of cytosolic Ca2+ concentration, [Ca2+]cyt, was investigated in plants differing in tolerance to hypoxia. The [Ca2+]cyt was measured by fluorescence microscopy in single protoplasts loaded with the calcium-fluoroprobe Fura 2-AM. Imposition of
anoxia led to a fast (within 3 min) significant elevation of [Ca2+]cyt in rice leaf protoplasts. A tenfold drop in the external Ca2+ concentration (to 0.1 mM) resulted in considerable decrease of the [Ca2+]cyt shift. Rice root protoplasts reacted upon anoxia with higher amplitude. Addition of plasma membrane (verapamil, La3+ and EGTA) and intracellular membrane Ca2+-channel antagonists (Li+, ruthenium red and cyclosporine A) reduced the anoxic Ca2+-accumulation in rice. Wheat protoplasts responded to anoxia by smaller changes of [Ca2+]cyt. In wheat leaf protoplasts, the amplitude of the Ca2+-shift little depended on the external level of Ca2+. Wheat root protoplasts were characterized by a small shift of [Ca2+]cyt under anoxia. Plasmalemma Ca2+-channel blockers had little effect on the elevation of cytosolic Ca2+ in wheat protoplasts. Intact rice seedlings absorbed Ca2+ from the external medium under anoxic treatment. On the contrary, wheat seedlings were characterized by leakage of Ca2+. Verapamil abolished the Ca2+ influx in rice roots and Ca2+ efflux from wheat roots. Anoxia-induced [Ca2+]cyt elevation was high particularly in rice, a hypoxia-tolerant species. In conclusion, both external and internal Ca2+ stores are important for anoxic [Ca2+]cyt elevation in rice, whereas the hypoxia-intolerant wheat does not require external sources for [Ca2+]cyt rise. Leaf and root protoplasts similarly responded to anoxia, independent of their organ origin. 相似文献
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996.
Shen L Park EJ Kondratyuk TP Guendisch D Marler L Pezzuto JM Wright AD Sun D 《Bioorganic & medicinal chemistry》2011,19(21):6182-6195
Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-β-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-β-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-α-induced NFκB activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 μM [the concentration to double the activity (CD)=3.8 μM] and its corresponding R-isomer 6f had an IR value of 4.3 (CD=0.2 μM). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NFκB, with the half maximal inhibitory concentration (IC(50)) value of 4.8 μM, and also showed over 60% inhibition at 50 μM of NO production (IC(50)=2.8 μM). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC(50)=14.7 μM). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC(50)=10.5 μM). 相似文献
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998.
Kumar P Yang M Haynes BC Skowyra ML Doering TL 《Current opinion in structural biology》2011,21(5):597-602
Cryptococcus neoformans, a basidiomycete yeast and opportunistic pathogen, expends significant biosynthetic effort on construction of a polysaccharide capsule with a radius that may be many times that of the cell. Beyond posing a stimulating challenge in terms of defining biosynthetic pathways, the capsule is required for this yeast to cause fatal disease. This combination has focused the attention of researchers on this system. Here we briefly review two aspects of the rapidly advancing field of capsule synthesis: the extensive variation that occurs in capsule polymers and the regulation of capsule biosynthesis. 相似文献
999.
Camille Martinez-Almoyna Gabin Piton Sylvain Abdulhak Louise Boulangeat Philippe Choler Thierry Delahaye Cédric Dentant Arnaud Foulquier Jérôme Poulenard Virgile Noble Julien Renaud Maxime Rome Amélie Saillard The ORCHAMP Consortium Wilfried Thuiller Tamara Münkemüller 《Ecography》2020,43(10):1550-1559
While soil ecosystems undergo important modifications due to global change, the effect of soil properties on plant distributions is still poorly understood. Plant growth is not only controlled by soil physico-chemistry but also by microbial activities through the decomposition of organic matter and the recycling of nutrients essential for plants. A growing body of evidence also suggests that plant functional traits modulate species’ response to environmental gradients. However, no study has yet contrasted the importance of soil physico-chemistry, microbial activities and climate on plant species distributions, while accounting for how plant functional traits can influence species-specific responses. Using hierarchical effects in a multi-species distribution model, we investigate how four functional traits related to resource acquisition (plant height, leaf carbon to nitrogen ratio, leaf dry matter content and specific leaf area) modulate the response of 44 plant species to climatic variables, soil physico-chemical properties and microbial decomposition activity (i.e. exoenzymatic activities) in the French Alps. Our hierarchical trait-based model allowed to predict well 41 species according to the TSS statistic. In addition to climate, the combination of soil C/N, as a measure of organic matter quality, and exoenzymatic activity, as a measure of microbial decomposition activity, strongly improved predictions of plant distributions. Plant traits played an important role. In particular, species with conservative traits performed better under limiting nutrient conditions but were outcompeted by exploitative plants in more favorable environments. We demonstrate tight associations between microbial decomposition activity, plant functional traits associated to different resource acquisition strategies and plant distributions. This highlights the importance of plant–soil linkages for mountain plant distributions. These results are crucial for biodiversity modelling in a world where both climatic and soil systems are undergoing profound and rapid transformations. 相似文献