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991.
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994.
Mamede GL Araújo NA Schneider CM de Araújo JC Herrmann HJ 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(19):7191-7195
Sustainability of communities, agriculture, and industry is strongly dependent on an effective storage and supply of water resources. In some regions the economic growth has led to a level of water demand that can only be accomplished through efficient reservoir networks. Such infrastructures are not always planned at larger scale but rather made by farmers according to their local needs of irrigation during droughts. Based on extensive data from the upper Jaguaribe basin, one of the world's largest system of reservoirs, located in the Brazilian semiarid northeast, we reveal that surprisingly it self-organizes into a scale-free network exhibiting also a power-law in the distribution of the lakes and avalanches of discharges. With a new self-organized-criticality-type model we manage to explain the novel critical exponents. Implementing a flow model we are able to reproduce the measured overspill evolution providing a tool for catastrophe mitigation and future planning. 相似文献
995.
Carotenoid oxidation products are stress signals that mediate gene responses to singlet oxygen in plants 总被引:1,自引:0,他引:1
Ramel F Birtic S Ginies C Soubigou-Taconnat L Triantaphylidès C Havaux M 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(14):5535-5540
(1)O(2) (singlet oxygen) is a reactive O(2) species produced from triplet excited chlorophylls in the chloroplasts, especially when plants are exposed to excess light energy. Similarly to other active O(2) species, (1)O(2) has a dual effect: It is toxic, causing oxidation of biomolecules, and it can act as a signal molecule that leads to cell death or to acclimation. Carotenoids are considered to be the main (1)O(2) quenchers in chloroplasts, and we show here that light stress induces the oxidation of the carotenoid β-carotene in Arabidopsis plants, leading to the accumulation of different volatile derivatives. One such compound, β-cyclocitral, was found to induce changes in the expression of a large set of genes that have been identified as (1)O(2) responsive genes. In contrast, β-cyclocitral had little effect on the expression of H(2)O(2) gene markers. β-Cyclocitral-induced reprogramming of gene expression was associated with an increased tolerance to photooxidative stress. The results indicate that β-cyclocitral is a stress signal produced in high light that is able to induce defense mechanisms and represents a likely messenger involved in the (1)O(2) signaling pathway in plants. 相似文献
996.
p63-microRNA feedback in keratinocyte senescence 总被引:1,自引:0,他引:1
Rivetti di Val Cervo P Lena AM Nicoloso M Rossi S Mancini M Zhou H Saintigny G Dellambra E Odorisio T Mahé C Calin GA Candi E Melino G 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(4):1133-1138
We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR-130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated β-galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas ΔNp63 expression was inhibited by miR-130b. We also found that ΔNp63α inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth-promoting strategy of ΔNp63α in epidermal proliferating cells. 相似文献
997.
Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo 总被引:1,自引:0,他引:1
Gotot J Gottschalk C Leopold S Knolle PA Yagita H Kurts C Ludwig-Portugall I 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(26):10468-10473
The mechanisms by which regulatory T cells (T(regs)) suppress autoantibody production are unclear. Here we have addressed this question using transgenic mice expressing model antigens in the kidney. We report that T(regs) were essential and sufficient to suppress autoreactive B cells in an antigen-specific manner and to prevent them from producing autoantibodies. Most of this suppression was mediated through the inhibitory cell-surface-molecule programmed death-1 (PD-1). Suppression required PD-1 expression on autoreactive B cells and expression of the two PD-1 ligands on T(regs). PD-1 ligation inhibited activation of autoreactive B cells, suppressed their proliferation, and induced their apoptosis. Intermediate PD-1(+) cells, such as T helper cells, were dispensable for suppression. These findings demonstrate in vivo that T(regs) use PD-1 ligands to directly suppress autoreactive B cells, and they identify a previously undescribed peripheral B-cell tolerance mechanism against tissue autoantigens. 相似文献
998.
AJ Geall A Verma GR Otten CA Shaw A Hekele K Banerjee Y Cu CW Beard LA Brito T Krucker DT O'Hagan M Singh PW Mason NM Valiante PR Dormitzer SW Barnett R Rappuoli JB Ulmer CW Mandl 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(36):14604-14609
Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted. 相似文献
999.
Zhao Y Biertümpfel C Gregory MT Hua YJ Hanaoka F Yang W 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(19):7269-7274
Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase η (hPol η). Here, we report crystal structures of hPol η complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol η is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol η differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol η undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol η is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol η is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance. 相似文献
1000.
Stewart JD Marchan R Lesjak MS Lambert J Hergenroeder R Ellis JK Lau CH Keun HC Schmitz G Schiller J Eibisch M Hedberg C Waldmann H Lausch E Tanner B Sehouli J Sagemueller J Staude H Steiner E Hengstler JG 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(21):8155-8160
Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention. 相似文献