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91.
Kerry-Ann da Costa Kiranmai S. Rai Corneliu N. Craciunescu Komal Parikh Mihai G. Mehedint Lisa M. Sanders Audrey McLean-Pottinger Steven H. Zeisel 《The Journal of biological chemistry》2010,285(2):1008-1015
The development of fetal brain is influenced by nutrients such as docosahexaenoic acid (DHA, 22:6) and choline. Phosphatidylethanolamine-N-methyltransferase (PEMT) catalyzes the biosynthesis of phosphatidylcholine from phosphatidylethanolamine enriched in DHA and many humans have functional genetic polymorphisms in the PEMT gene. Previously, it was reported that Pemt−/− mice have altered hippocampal development. The present study explores whether abnormal phosphatidylcholine biosynthesis causes altered incorporation of DHA into membranes, thereby influencing brain development, and determines whether supplemental dietary DHA can reverse some of these changes. Pregnant C57BL/6 wild type (WT) and Pemt−/− mice were fed a control diet, or a diet supplemented with 3 g/kg of DHA, from gestational day 11 to 17. Brains from embryonic day 17 fetuses derived from Pemt−/− dams fed the control diet had 25–50% less phospholipid-DHA as compared with WT (p < 0.05). Also, they had 60% more neural progenitor cell proliferation (p < 0.05), 60% more neuronal apoptosis (p < 0.01), and 30% less calretinin expression (p < 0.05; a marker of neuronal differentiation) in the hippocampus compared with WT. The DHA-supplemented diet increased fetal brain Pemt−/− phospholipid-DHA to WT levels, and abrogated the neural progenitor cell proliferation and apoptosis differences. Although this diet did not change proliferation in the WT group, it halved the rate of apoptosis (p < 0.05). In both genotypes, the DHA-supplemented diet increased calretinin expression 2-fold (p < 0.05). These results suggest that the changes in hippocampal development in the Pemt−/− mouse could be mediated by altered DHA incorporation into membrane phospholipids, and that maternal dietary DHA can influence fetal brain development. 相似文献
92.
Nelson C. Di Paolo Lisa K. Baldwin Eric E. Irons Thalia Papayannopoulou Stephen Tomlinson Dmitry M. Shayakhmetov 《PLoS pathogens》2014,10(3)
Inflammation is a highly coordinated host response to infection, injury, or cell stress. In most instances, the inflammatory response is pro-survival and is aimed at restoring physiological tissue homeostasis and eliminating invading pathogens, although exuberant inflammation can lead to tissue damage and death. Intravascular injection of adenovirus (Ad) results in virus accumulation in resident tissue macrophages that trigger activation of CXCL1 and CXCL2 chemokines via the IL-1α-IL-1RI signaling pathway. However, the mechanistic role and functional significance of this pathway in orchestrating cellular inflammatory responses to the virus in vivo remain unclear. Resident metallophilic macrophages expressing macrophage receptor with collagenous structure (MARCO+) in the splenic marginal zone (MZ) play the principal role in trapping Ad from the blood. Here we show that intravascular Ad administration leads to the rapid recruitment of Ly-6G+7/4+ polymorphonuclear leukocytes (PMNs) in the splenic MZ, the anatomical compartment that remains free of PMNs when these cells are purged from the bone marrow via a non-inflammatory stimulus. Furthermore, PMN recruitment in the splenic MZ resulted in elimination of virus-containing cells. IL-1α-IL-1RI signaling is only partially responsible for PMN recruitment in the MZ and requires CXCR2, but not CXCR1 signaling. We further found reduced recruitment of PMNs in the splenic MZ in complement C3-deficient mice, and that pre-treatment of IL-1α-deficient, but not wild-type mice, with complement inhibitor CR2-Crry (inhibits all complement pathways at C3 activation) or CR2-fH (inhibits only the alternative complement activation pathway) prior to Ad infection, abrogates PMN recruitment to the MZ and prevents elimination of MARCO+ macrophages from the spleen. Collectively, our study reveals a non-redundant role of the molecular factors of innate immunity – the chemokine-activating IL-1α-IL-1RI-CXCR2 axis and complement – in orchestrating local inflammation and functional cooperation of PMNs and resident macrophages in the splenic MZ, which collectively contribute to limiting disseminated pathogen spread via elimination of virus-containing cells. 相似文献
93.
Hildur Helgadottir Emilia Andersson Lisa Villabona Lena Kanter Henk van der Zanden Geert W. Haasnoot Barbara Seliger Kjell Bergfeldt Johan Hansson Boel Ragnarsson-Olding Rolf Kiessling Giuseppe Valentino Masucci 《Cancer immunology, immunotherapy : CII》2009,58(10):1599-1608
Purpose We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate
cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with
stage III–IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the
prognosis in stage III–IV malignant melanoma patients.
Patients and methods A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles
in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined
by Kaplan–Meier and Cox analysis.
Results The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival
rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02–4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype
(HR = 0.40; CI = 0.17–0.90; P = 0.02).
Conclusions Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour
control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding
poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between
tumour clones escape and immune surveillance ending up with a rapid disease progression.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
94.
Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer’s disease
Barbara Bettegazzi Laura Sebastian Monasor Serena Bellani Franca Codazzi Lisa Michelle Restelli Alessio Vittorio Colombo Nikolaus Deigendesch Stephan Frank Takashi Saito Takaomi C. Saido Sven Lammich Sabina Tahirovic Fabio Grohovaz Daniele Zacchetti 《Cell death & disease》2021,12(8)
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.Subject terms: Kinases, Alzheimer''s disease, Neuronal physiology, Pathogenesis 相似文献
95.
Alamethicin is a 19-amino-acid residue hydrophobic peptide of the peptaibol family that has been the object of numerous studies for its ability to produce voltage-dependent ion channels in membranes. In this work, for the first time electron paramagnetic resonance spectroscopy was applied to study the interaction of alamethicin with oriented bicelles. We highlighted the effects of increasing peptide concentrations on both the peptide and the membrane in identical conditions, by adopting a twofold spin labeling approach, placing a nitroxide moiety either on the peptide or on the phospholipids. The employment of bicelles affords additional spectral resolution, thanks to the formation of a macroscopically oriented phase that allows to gain information on alamethicin orientation and dynamics. Moreover, the high viscosity of the bicellar solution permits the investigation of the peptide aggregation properties at physiological temperature. We observed that, at 35 °C, alamethicin adopts a transmembrane orientation with the peptide axis forming an average angle of 25° with respect to the bilayer normal. Moreover, alamethicin maintains its dynamics and helical tilt constant at all concentrations studied. On the other hand, by increasing the peptide concentration, the bilayer experiences an exponential decrease of the order parameter, but does not undergo micellization, even at the highest peptide to lipid ratio studied (1:20). Finally, the aggregation of the peptide at physiological temperature shows that the peptide is monomeric at peptide to lipid ratios lower than 1:50, then it aggregates with a rather broad distribution in the number of peptides (from 6 to 8) per oligomer. 相似文献
96.
Determining the importance of stopover and staging areas to migrating shorebirds (Aves: Charadriiformes) is essential if such habitats are to be successfully protected. Migration chronology, species composition, length of stay, body condition, and estimated total abundance of shorebirds during spring and fall migratory periods of 2008 and 2009 were documented on Akimiski Island, Nunavut, Canada. Fourteen shorebird species were observed during spring point counts and 18 during fall. Semipalmated (Calidris pusilla) and White-rumped (C. fuscicollis) Sandpipers comprised about 80?% of all individuals observed. A greater number of species and individuals were observed during fall than spring in both years. Radio-transmitters attached to juvenile Semipalmated and Least (C. minutilla) Sandpipers indicated highly variable lengths of stay ranging up to 26?days in both species (Semipalmated Sandpiper averaged 6.5?±?2.67?days, n?=?12; Least Sandpipers averaged 7.25?±?3.79?days, n?=?8). In 2009, Semipalmated Sandpipers captured and weighed later in the season were significantly heavier than those captured earlier suggesting that this species is refueling while on Akimiski Island. A fall migration seasonal density of 5,267 (2,193–8,341) shorebirds/km2 was estimated given a residence probability (i.e., the probability of an individual being present in consecutive counts) of 0.906?±?0.181. Assuming similar habitat value and shorebird density, an extrapolation of the seasonal plot density of 5,267 birds/km2 to the total 192?km2 mudflat habitat on Akimiski Island yields an estimate of 1,011,264 (421,098–1,601,429) shorebirds during fall migration, making Akimiski Island of Hemispheric importance as a staging site for migrant arctic-breeding shorebirds. 相似文献
97.
Miller MW Wolfe LL Sirochman TM Sirochman MA Jewell JE Williams ES 《Journal of wildlife diseases》2012,48(2):526-529
We orally inoculated white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus) with a standardized, conspecific prion dose and collected biologic samples throughout the disease course. Mule deer (PRNP genotype 225SS) and PRNP genotype 96GG white-tailed deer succumbed along similar trajectories, but 96GS- and 96SS-genotype individuals tended to survive longer. 相似文献
98.
MD Barense II Groen AC Lee LK Yeung SM Brady M Gregori N Kapur TJ Bussey LM Saksida RN Henson 《Neuron》2012,75(1):157-167
Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain. 相似文献
99.
Olivier Maurin Artemis Anest Sidonie Bellot Edward Biffin Grace Brewer Tristan Charles-Dominique Robyn S. Cowan Steven Dodsworth Niroshini Epitawalage Berta Gallego Augusto Giaretta Renato Goldenberg Deise J.P. Gonçalves Shirley Graham Peter Hoch Fiorella Mazine Yee Wen Low Catherine McGinnie Fabián A. Michelangeli Sarah Morris Darin S. Penneys Oscar Alejandro Pérez Escobar Yohan Pillon Lisa Pokorny Gustavo Shimizu Vanessa G. Staggemeier Andrew H. Thornhill Kyle W. Tomlinson Ian M. Turner Thais Vasconcelos Peter G. Wilson Alexandre R. Zuntini William J. Baker Félix Forest Eve Lucas 《American journal of botany》2021,108(7):1087-1111
100.