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71.
72.
Zhu C Xu F Wang X Shibata M Uchiyama Y Blomgren K Hagberg H 《Journal of neurochemistry》2006,96(4):1016-1027
Sex-related brain injury was evaluated after unilateral hypoxia-ischaemia (HI) in C57/BL6 mice on postnatal day (P) 5, 9, 21 or 60, corresponding developmentally to premature, term, juvenile and adult human brains. There was no sex difference in brain injury when the insult was severe, as evaluated by pathological scoring or tissue loss, but when the insult was moderate, adult (P60) females displayed less injury. In the immature (P9) male brains, neurones displayed a more pronounced translocation of apoptosis-inducing factor (AIF) (loss of AIF from the mitochondrial fraction and increase in nuclear AIF) after HI, whereas the female brain neurones displayed a stronger activation of caspase 3 (more pronounced loss of pro-caspase 3, increase in cleaved caspase 3 and increase in caspase 3 enzymatic activity). Two other mechanisms of injury, peroxynitrite-induced formation of nitrotyrosine and autophagy, were no different between males and females at P9. These data show that the CNS is more resistant to HI in adult females compared with males, whereas no sex differences were found in the extent of injury in neonatal mice. However, critical sex-dependent differences were demonstrated in vivo with regard to cellular, apoptosis-related mechanisms. 相似文献
73.
Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells 总被引:2,自引:0,他引:2
Jaster R Lichte P Fitzner B Brock P Glass A Karopka T Gierl L Koczan D Thiesen HJ Sparmann G Emmrich J Liebe S 《Journal of cellular and molecular medicine》2005,9(3):670-682
Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies. 相似文献
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75.
Communities are complex and dynamic systems that change with time. The first attempts to explain how they were structured involve contemporary phenomena like ecological interactions between species (e.g., competition and predation) and led to the competition-predation hypothesis. Recently, the deep history hypothesis has emerged, which suggests that profound differences in the evolutionary history of organisms resulted in a number of ecological features that remain largely on species that are part of existing communities. Nevertheless, both phylogenetic structure and ecological interactions can act together to determine the structure of a community. Because diet is one of the main niche axes, in this study we evaluated, for the first time, the impact of ecological and phylogenetic factors on the diet of Neotropical snakes from the subtropical-temperate region of South America. Additionally, we studied their relationship with morphological and environmental aspects to understand the natural history and ecology of this community. A canonical phylogenetical ordination analysis showed that phylogeny explained most of the variation in diet, whereas ecological characters explained very little of this variation. Furthermore, some snakes that shared the habitat showed some degree of diet convergence, in accordance with the competition-predation hypothesis, although phylogeny remained the major determinant in structuring this community. The clade with the greatest variability was the subfamily Dipsadinae, whose members had a very different type of diet, based on soft-bodied invertebrates. Our results are consistent with the deep history hypothesis, and we suggest that the community under study has a deep phylogenetic effect that explains most of the variation in the diet. 相似文献
76.
Carmen S. M. Yong Janelle Sharkey Belinda Duscio Ben Venville Wei-Zen Wei Richard F. Jones Clare Y. Slaney Gisela Mir Arnau Anthony T. Papenfuss Jan Schr?der Phillip K. Darcy Michael H. Kershaw 《PloS one》2015,10(9)
The development of antigen-targeted therapeutics is dependent on the preferential expression of tumor-associated antigens (TAA) at targetable levels on the tumor. Tumor-associated antigens can be generated de novo or can arise from altered expression of normal basal proteins, such as the up-regulation of human epidermal growth factor receptor 2 (Her2/ErbB2). To properly assess the development of Her2 therapeutics in an immune tolerant model, we previously generated a transgenic mouse model in which expression of the human Her2 protein was present in both the brain and mammary tissue. This mouse model has facilitated the development of Her2 targeted therapies in a clinically relevant and suitable model. While heterozygous Her2+/- mice appear to develop in a similar manner to wild type mice (Her2-/-), it has proven difficult to generate homozygous Her2+/+ mice, potentially due to embryonic lethality. In this study, we performed whole genome sequencing to determine if the integration site of the Her2 transgene was responsible for this lethality. Indeed, we report that the Her2 transgene had integrated into the Pds5b (precocious dissociation of sisters) gene on chromosome 5, as a 162 copy concatemer. Furthermore, our findings demonstrate that Her2+/+ mice, similar to Pds5b-/- mice, are embryonic lethal and confirm the necessity for Pds5b in embryonic development. This study confirms the value of whole genome sequencing in determining the integration site of transgenes to gain insight into associated phenotypes. 相似文献
77.
Bianca Schmid Melanie Rinas Alessia Ruggieri Eliana Gisela Acosta Marie Bartenschlager Antje Reuter Wolfgang Fischl Nathalie Harder Jan-Philip Bergeest Michael Flossdorf Karl Rohr Thomas H?fer Ralf Bartenschlager 《PLoS pathogens》2015,11(12)
Dengue virus (DENV) is the most common mosquito-transmitted virus infecting ~390 million people worldwide. In spite of this high medical relevance, neither a vaccine nor antiviral therapy is currently available. DENV elicits a strong interferon (IFN) response in infected cells, but at the same time actively counteracts IFN production and signaling. Although the kinetics of activation of this innate antiviral defense and the timing of viral counteraction critically determine the magnitude of infection and thus disease, quantitative and kinetic analyses are lacking and it remains poorly understood how DENV spreads in IFN-competent cell systems. To dissect the dynamics of replication versus antiviral defense at the single cell level, we generated a fully viable reporter DENV and host cells with authentic reporters for IFN-stimulated antiviral genes. We find that IFN controls DENV infection in a kinetically determined manner that at the single cell level is highly heterogeneous and stochastic. Even at high-dose, IFN does not fully protect all cells in the culture and, therefore, viral spread occurs even in the face of antiviral protection of naïve cells by IFN. By contrast, a vaccine candidate DENV mutant, which lacks 2’-O-methylation of viral RNA is profoundly attenuated in IFN-competent cells. Through mathematical modeling of time-resolved data and validation experiments we show that the primary determinant for attenuation is the accelerated kinetics of IFN production. This rapid induction triggered by mutant DENV precedes establishment of IFN-resistance in infected cells, thus causing a massive reduction of virus production rate. In contrast, accelerated protection of naïve cells by paracrine IFN action has negligible impact. In conclusion, these results show that attenuation of the 2’-O-methylation DENV mutant is primarily determined by kinetics of autocrine IFN action on infected cells. 相似文献
78.
Milena Gisela Casafús Marília Melo Favalesso Micaela Andrea Gritti Juan Manuel Coronel Ana Tereza Bittencourt Guimares Maria Elisa Peichoto 《PLoS neglected tropical diseases》2021,15(7)
BackgroundEnvenomation by the South American Lonomia saturniid caterpillars, named lonomism, constitutes an emerging and somewhat neglected public health issue in Argentina and neighboring countries. Considering that there is an intricate relationship between environment and human health in such cases, this study aimed to analyze the eco-epidemiological profile of 40 accidents and 33 occurrences of Lonomia spp. in Misiones (Argentina) between January 2014 and May 2020.Methodology/Principal findingsWe described the eco-epidemiological variables and characterized the abiotic scenario of such cases. Additionally, we obtained a density map that shows the punctual intensity of Lonomia records throughout Misiones. Most of the accidents occurred in the Department of Guaraní and involved male victims younger than 20 years old. The accidental/occasional occurrence of Lonomia spp. (considering both adult and caterpillar stages together) was significantly higher in the rural area, whereas only adult specimens were found in urban areas. We determined that the presence of this insect in Misiones is positively related to higher temperatures and solar radiation, and larger precipitation and evapotranspiration throughout the year.Conclusion/SignificanceThis study represents an initial step towards the global understanding of lonomism as a public health problem in Argentina. It provides a map of the risk level for this envenomation in Misiones, which could help authorities address public health policy efforts to implement sustainable strategies for prevention and response to this threat in Northeastern Argentina and neighboring regions. 相似文献
79.
Intraskeletal isotopic compositions (δ13C, δ15N) of bone collagen: Nonpathological and pathological variation 下载免费PDF全文
Karyn C. Olsen Christine D. White Fred J. Longstaffe Kristin von Heyking George McGlynn Gisela Grupe Frank J. Rühli 《American journal of physical anthropology》2014,153(4):598-604
Paleodiet research traditionally interprets differences in collagen isotopic compositions (δ13C, δ15N) as indicators of dietary distinction even though physiological processes likely play some role in creating variation. This research investigates the degree to which bone collagen δ13C and δ15N values normally vary within the skeleton and examines the influence of several diseases common to ancient populations on these isotopic compositions. The samples derive from two medieval German cemeteries and one Swiss reference collection and include examples of metabolic disease (rickets/osteomalacia), degenerative joint disease (osteoarthritis), trauma (fracture), infection (osteomyelitis), and inflammation (periostitis). A separate subset of visibly nonpathological skeletal elements from the German collections established normal intraindividual variation. For each disease type, tests compared bone lesion samples to those near and distant to the lesions sites. Results show that normal (nonpathological) skeletons exhibit limited intraskeletal variation in carbon‐ and nitrogen‐isotope ratios, suggesting that sampling of distinct elements is appropriate for paleodiet studies. In contrast, individuals with osteomyelitis, healed fractures, and osteoarthritis exhibit significant intraskeletal differences in isotope values, depending on whether one is comparing lesions to near or to distant sites. Skeletons with periostitis result in significant intraskeletal differences in nitrogen isotope values only, while those with rickets/osteomalacia do not exhibit significant intraskeletal differences. Based on these results, we suggest that paleodiet researchers avoid sampling collagen at or close to lesion sites because the isotope values may be reflecting both altered metabolic processes and differences in diet relative to others in the population. Am J Phys Anthropol 153:598–604, 2014. © 2013 Wiley Periodicals, Inc. 相似文献
80.
Merz Felicitas Müller Mareike Taucher-Scholz Gisela Rödel Franz Stöcker Horst Schopow Kosta Laprell Laura Dehghani Faramarz Durante Marco Bechmann Ingo 《Radiation and environmental biophysics》2010,49(3):457-462
The aim of this interdisciplinary project is to establish slice culture preparations from rodents and humans as a new model
system for studying effects of X-rays and heavy ions within normal and tumor tissues. The advantage of such slice cultures
relies on the conservation of an organotypic environment, the easy treatment and observation by live-imaging microscopy, and
the independence from genetic immortalization strategies used to generate cell lines. Rat brains as well as human tumors were
cut into 300-μm-thick sections and cultivated in an incubator in a humidified atmosphere at 37°C. This is realized by a membrane-based
culture system with a liquid–air interface. With this system, it is possible to keep rodent slices viable for several months.
Human brain tumor slices remained vital for at least 21 days. Slices were irradiated with X-rays at the radiation facility
of the University Hospital in Frankfurt/Main at doses up to 40 Gy. Heavy ion irradiations were performed at GSI (Darmstadt)
with different ions, energies, and doses. The irradiated slices were analyzed by 3D-confocal microscopy following immunostaining
for DNA damage, microglia, and proliferation markers. The phosphorylated histone γH2AX proved to be suitable for the detection
of ion traversals in this system. 相似文献