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Mohammad Jaber Miriam Maoz Arun Kancharla Daniel Agranovich Tamar Peretz Sorina Grisaru-Granovsky Beatrice Uziely Rachel Bar-Shavit 《Cellular and molecular life sciences : CMLS》2014,71(13):2517-2533
Mammalian protease-activated-receptor-1 and -2 (PAR1 and PAR2) are activated by proteases found in the flexible microenvironment of a tumor and play a central role in breast cancer. We propose in the present study that PAR1 and PAR2 act together as a functional unit during malignant and physiological invasion processes. This notion is supported by assessing pro-tumor functions in the presence of short hairpin; shRNA knocked-down hPar2 or by the use of a truncated PAR2 devoid of the entire cytoplasmic tail. Silencing of hPar2 by shRNA-attenuated thrombin induced PAR1 signaling as recapitulated by inhibiting the assembly of Etk/Bmx or Akt onto PAR1-C-tail, by thrombin-instigated colony formation and invasion. Strikingly, shRNA-hPar2 also inhibited the TFLLRN selective PAR1 pro-tumor functions. In addition, while evaluating the physiological invasion process of placenta extravillous trophoblast (EVT) organ culture, we observed inhibition of both thrombin or the selective PAR1 ligand; TFLLRNPNDK induced EVT invasion by shRNA-hPar2 but not by scrambled shRNA-hPar2. In parallel, when a truncated PAR2 was utilized in a xenograft mouse model, it inhibited PAR1–PAR2-driven tumor growth in vivo. Similarly, it also attenuated the interaction of Etk/Bmx with the PAR1-C-tail in vitro and decreased markedly selective PAR1-induced Matrigel invasion. Confocal images demonstrated co-localization of PAR1 and PAR2 in HEK293T cells over-expressing YFP-hPar2 and HA-hPar1. Co-immuno-precipitation analyses revealed PAR1-PAR2 complex formation but no PAR1-CXCR4 complex was formed. Taken together, our observations show that PAR1 and PAR2 act as a functional unit in tumor development and placenta-uterus interactions. This conclusion may have significant consequences on future breast cancer therapeutic modalities and improved late pregnancy outcome. 相似文献
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Panizzi JR Becker-Heck A Castleman VH Al-Mutairi DA Liu Y Loges NT Pathak N Austin-Tse C Sheridan E Schmidts M Olbrich H Werner C Häffner K Hellman N Chodhari R Gupta A Kramer-Zucker A Olale F Burdine RD Schier AF O'Callaghan C Chung EM Reinhardt R Mitchison HM King SM Omran H Drummond IA 《Nature genetics》2012,44(6):714-719
Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated. 相似文献
5.
Unusual activity of the Sun during recent decades compared to the previous 11,000 years 总被引:4,自引:0,他引:4
Direct observations of sunspot numbers are available for the past four centuries, but longer time series are required, for example, for the identification of a possible solar influence on climate and for testing models of the solar dynamo. Here we report a reconstruction of the sunspot number covering the past 11,400 years, based on dendrochronologically dated radiocarbon concentrations. We combine physics-based models for each of the processes connecting the radiocarbon concentration with sunspot number. According to our reconstruction, the level of solar activity during the past 70 years is exceptional, and the previous period of equally high activity occurred more than 8,000 years ago. We find that during the past 11,400 years the Sun spent only of the order of 10% of the time at a similarly high level of magnetic activity and almost all of the earlier high-activity periods were shorter than the present episode. Although the rarity of the current episode of high average sunspot numbers may indicate that the Sun has contributed to the unusual climate change during the twentieth century, we point out that solar variability is unlikely to have been the dominant cause of the strong warming during the past three decades. 相似文献
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Stafford Beer 《Systemic Practice and Action Research》1997,10(4):365-380
This paper examines the inadequacy of managerial models to manage our world, especially in ethical matters. It starts by illustrating the reductionistic nature of these models. They gradually take the place of the real world in our minds and become a surrogate world. While this surrogate world seems to perform perfectly well, the real world is far out of control. Next the paper states that understanding and, therefore, models are timeless. The article explains how ancient misconceptions about change find their correspondence in modern misconceptions about ethical decisions. This is the culpabliss error. The author finally argues that the ethical relationships between a decision or action and its consequences must be dealt with in a cybernetic way. 相似文献
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General systems formalizations of expert knowledge play a foundational role in the process of knowledge engineering of intelligent systems. Canonical definitions of systems (knowledge structures) which have been arrived at by a crossdisciplinary inductive modeling process are shown to be the basis for the modeling of certain generic categories of expert reasoning processes which are of current interest in knowledge engineering. The methodology for transforming the representation of knowledge expressed in general systems formalizations to the representation of that knowledge in expert systems is also developed. In particular, transformations from general systems formalizations into frames are presented. 相似文献
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Stafford Beer 《Systemic Practice and Action Research》1990,3(2):115-124
This festschrift paper, written in honour of Russell Ackoff, hinges on three of his characteristic approaches: the use of fables, his acceptance of messes as distinct from well-formulated problems, and his concept of idealized planning. Current thoughts of the author, dealing respectively with recursive logic, the implementation of change, and the theory of democratic organization, are attached to these hinges and among them, express his own theme as to a relativity of systems. 相似文献
10.
Samuel Cardozo Ribeiro Diego Alves Teles Daniel Oliveira Mesquita Waltécio de Oliveira Almeida Luciano Alves dos Anjos Miriam Camargo Guarnieri 《Journal of Natural History》2019,53(39-40):2365-2377
ABSTRACTWe evaluated the activity period, thermal ecology, habitats, and preference for microhabitats of the skink Mabuya arajara in a humid forest environment on the slope of the Araripe Plateau, Brazil. A total of 283 lizards were observed. The lizards were found to be diurnally active (unimodal type pattern), with peak activity during the hottest hours of the day (1100 to 1200). About habitat use, the majority of individuals (73.8% N = 209) were recorded in the narrow transitional area, in the edges of the forest; while 26.4% of individuals were observed in open areas and no observations were made in dense forest. Seven different types of microhabitats were used, with fallen palm leaves (Arecaceae) being the preferred (47.7% N = 135). Considering all lizards, microhabitat niche breadth was 3.27. Males and females presented a high overlap (0.95) in microhabitat use. The average Tc recorded for M. arajara was 32.06 ± 2.72°C. Body size (SVL) did not influence body temperature (F = 0.51, P = > 0.05). Most of the animals were observed with their bodies completely exposed (67.84%, N = 192), 18.37% (N = 52) were semi-exposed and 13.79% (N = 39) were in shelters. Among animals with some degree of sunlight exposure, 57.59% (N = 163) were in shadows, 25.10% (N = 71) were under sunlight filtered by vegetation, and 17.31% (N = 49) were under direct sunlight.A review of the ecology of Mabuya spp. shows that several features appear to be conserved among members of the genus. 相似文献