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61.
62.
PARP-1 Regulates Metastatic Melanoma through Modulation of Vimentin-induced Malignant Transformation
María Isabel Rodríguez Andreína Peralta-Leal Francisco O'Valle José Manuel Rodriguez-Vargas Ariannys Gonzalez-Flores Jara Majuelos-Melguizo Laura López Santiago Serrano Antonio García de Herreros Juan Carlos Rodríguez-Manzaneque Rubén Fernández Raimundo G. del Moral José Mariano de Almodóvar F. Javier Oliver 《PLoS genetics》2013,9(6)
PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells. 相似文献
63.
Temperature responses of the cockroach, Blaberus craniifer, to rapid changes of ambient temperature (Ta) have been studied. In static conditions at Ta = 27°C the body-to-ambient temperature difference was only 0.10 ± 0.07°C. Two test situations were used, either a ramp increase of Ta from 27 to 31°C (0.1°C/min) or “step” changes from 27 to 28°C and back (0.5°C/min). In both cases body temperature closely followed Newtonian model, the body time constants measured in various conditions being very similar: 543 ± 99 sec in ramp tests, 550 ± 68 sec and 542 ± 124 sec in rising and falling step tests respectively. It is concluded that in spite of evident differences between the cockroach and an inert solid, the Newtonian model adequately represents the thermal responses of this insect to moderate changes in ambient temperature. 相似文献
64.
As performance of halide perovskite devices progresses, the device structure becomes more complex with more layers. Molecular interfacial structures between different layers play an increasingly important role in determining the overall performance in a halide perovskite device. However, current understanding of such interfacial structures at a molecular level nondestructively is limited, partially due to a lack of appropriate analytical tools to probe buried interfacial molecular structures in situ. Here, sum frequency generation (SFG) vibrational spectroscopy, a state‐of‐the‐art nonlinear interface sensitive spectroscopy, is introduced to the halide perovskite research community and is presented as a powerful tool to understand molecule behavior at buried halide perovskite interfaces in situ. It is found that interfacial molecular orientations revealed by SFG can be directly correlated to halide perovskite device performance. Here how SFG can examine molecular structures (e.g., orientations) at the perovskite/hole transporting layer and perovskite/electron transporting layer interfaces is discussed. This will promote the use of SFG to investigate molecular structures of buried interfaces in various halide perovskite materials and devices in situ nondestructively with a sub‐monolayer interface sensitivity. Such research will help to elucidate structure–function relationships of buried interfaces, aiding in the rational design/development of halide perovskite materials/devices with improved performance. 相似文献
65.
Paulo R. L. Bittencourt Rafael S. Oliveira Antonio C. L. da Costa Andre L. Giles Ingrid Coughlin Patricia B. Costa David C. Bartholomew Leandro V. Ferreira Steel S. Vasconcelos Fernanda V. Barros Joao A. S. Junior Alex A. R. Oliveira Maurizio Mencuccini Patrick Meir Lucy Rowland 《Global Change Biology》2020,26(6):3569-3584
The fate of tropical forests under future climate change is dependent on the capacity of their trees to adjust to drier conditions. The capacity of trees to withstand drought is likely to be determined by traits associated with their hydraulic systems. However, data on whether tropical trees can adjust hydraulic traits when experiencing drought remain rare. We measured plant hydraulic traits (e.g. hydraulic conductivity and embolism resistance) and plant hydraulic system status (e.g. leaf water potential, native embolism and safety margin) on >150 trees from 12 genera (36 species) and spanning a stem size range from 14 to 68 cm diameter at breast height at the world's only long‐running tropical forest drought experiment. Hydraulic traits showed no adjustment following 15 years of experimentally imposed moisture deficit. This failure to adjust resulted in these drought‐stressed trees experiencing significantly lower leaf water potentials, and higher, but variable, levels of native embolism in the branches. This result suggests that hydraulic damage caused by elevated levels of embolism is likely to be one of the key drivers of drought‐induced mortality following long‐term soil moisture deficit. We demonstrate that some hydraulic traits changed with tree size, however, the direction and magnitude of the change was controlled by taxonomic identity. Our results suggest that Amazonian trees, both small and large, have limited capacity to acclimate their hydraulic systems to future droughts, potentially making them more at risk of drought‐induced mortality. 相似文献
66.
Zackie Aktary Andre Corvelo Camille Estrin Lionel Larue 《Pigment cell & melanoma research》2020,33(3):426-434
The Cre/loxP system is a powerful tool that has allowed the study of the effects of specific genes of interest in various biological settings. The Tyr::CreERT2 system allows for the targeted expression and activity of the Cre enzyme in the melanocyte lineage following treatment with tamoxifen, thus providing spatial and temporal control of the expression of specific target genes. Two independent transgenic mouse models, each containing a Tyr::CreERT2 transgene, have been generated and are widely used to study melanocyte transformation. In this study, we performed whole genome sequencing (WGS) on genomic DNA from the two Tyr::CreERT2 mouse models and identified their sites of integration in the C57BL/6 genome. Based on these results, we designed PCR primers to accurately, and efficiently, genotype transgenic mice. Finally, we discussed some of the advantages of each transgenic mouse model. 相似文献
67.
Muriel Cario Catherine Pain Priscilla Kaulanjan‐Checkmodine Daniela Masia Gabriele Delia Vincent Casoli Pierre Costet Jean‐Franois Goussot Vronique Guyonnet‐Duperat Alice Bibeyran Khaled Ezzedine Corinne Reymermier Valrie Andre‐Frei Alain Taieb 《Pigment cell & melanoma research》2020,33(3):435-445
Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF‐2 and keratin 5. In vitro analysis confirmed that FGF‐2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling–Degos Disease (DDD) have already been associated with the pheomelanosome–eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age‐related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders. 相似文献
68.
Berit Hassing Carla J. Eaton David Winter Kimberly A. Green Ulrike Brandt Matthew S. Savoian Carl H. Mesarich Andre Fleissner Barry Scott 《Molecular microbiology》2020,113(6):1101-1121
Although lipid signaling has been shown to serve crucial roles in mammals and plants, little is known about this process in filamentous fungi. Here we analyze the contribution of phospholipase D (PLD) and its product phosphatidic acid (PA) in hyphal morphogenesis and growth of Epichloë festucae and Neurospora crassa, and in the establishment of a symbiotic interaction between E. festucae and Lolium perenne. Growth of E. festucae and N. crassa PLD deletion strains in axenic culture, and for E. festucae in association with L. perenne, were analyzed by light-, confocal- and electron microscopy. Changes in PA distribution were analyzed in E. festucae using a PA biosensor and the impact of these changes on the endocytic recycling and superoxide production investigated. We found that E. festucae PldB, and the N. crassa ortholog, PLA-7, are required for polarized growth and cell fusion and contribute to ascospore development, whereas PldA/PLA-8 are dispensable for these functions. Exogenous addition of PA rescues the cell-fusion phenotype in E. festucae. PldB is also crucial for E. festucae to establish a symbiotic association with L. perenne. This study identifies a new component of the cell-cell communication and cell fusion signaling network for hyphal morphogenesis and growth of filamentous fungi. 相似文献
69.
Theresa Farhat Amel Dudakovic Jay H. Chung Andre J. van Wijnen Ren St‐Arnaud 《Journal of cellular physiology》2021,236(2):1195-1213
70.
Mario Gimona Maria Felice Brizzi Andre Boon Hwa Choo Massimo Dominici Sean M. Davidson Johannes Grillari Dirk M. Hermann Andrew F. Hill Dominique de Kleijn Ruenn Chai Lai Charles P. Lai Rebecca Lim Marta Monguió-Tortajada Maurizio Muraca Takahiro Ochiya Luis A. Ortiz Wei Seong Toh Yong Weon Yi Sai Kiang Lim 《Cytotherapy》2021,23(5):373-380
Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50–200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex “work-in-progress” MoA and to develop assays likely to be compliant with regulatory guidance for assay validation. 相似文献