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81.
Petrovas C Mueller YM Dimitriou ID Bojczuk PM Mounzer KC Witek J Altman JD Katsikis PD 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(7):4444-4453
Human immunodeficiency virus-specific CD8(+) T cells are highly sensitive to spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their ability to control HIV infection. To elucidate the mechanism behind this sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl-2 and Bcl-x(L) in HIV-specific CD8(+) T cells from HIV-infected individuals. Bcl-2 expression was markedly decreased in HIV-specific CD8(+) T cells compared with CMV-specific and total CD8(+) T cells from HIV-infected individuals as well as total CD8(+) T cells from healthy donors. CD8(+) T cell Bcl-2 levels inversely correlated with spontaneous and CD95/Fas-induced apoptosis of CD8(+) T cells from HIV-infected individuals. HIV-specific CD8(+) T cells also had significantly lower levels of Bcl-x(L) compared with CMV-specific CD8(+) T cells. Finally, IL-15 induces both Bcl-2 and Bcl-x(L) expression in HIV-specific and total CD8(+) T cells, and this correlated with apoptosis inhibition and increased survival in both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl-x(L) may play an important role in the increased sensitivity to apoptosis of HIV-specific CD8(+) T cells and suggest a possible mechanism by which IL-15 increases their survival. 相似文献
82.
Jacob F Ukegjini K Nixdorf S Ford CE Olivier J Caduff R Scurry JP Guertler R Hornung D Mueller R Fink DA Hacker NF Heinzelmann-Schwarz VA 《PloS one》2012,7(2):e31885
Background
Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands.Methodology/Principal Findings
We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8.Conclusions/Significance
Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets. 相似文献83.
Cristian Koepfli Lincoln Timinao Tiago Antao Alyssa E. Barry Peter Siba Ivo Mueller Ingrid Felger 《PloS one》2013,8(6)
Introduction
The importance of Plasmodium vivax in malaria elimination is increasingly being recognized, yet little is known about its population size and population genetic structure in the South Pacific, an area that is the focus of intensified malaria control.Methods
We have genotyped 13 microsatellite markers in 295 P. vivax isolates from four geographically distinct sites in Papua New Guinea (PNG) and one site from Solomon Islands, representing different transmission intensities.Results
Diversity was very high with expected heterozygosity values ranging from 0.62 to 0.98 for the different markers. Effective population size was high (12′872 to 19′533 per site). In PNG population structuring was limited with moderate levels of genetic differentiation. F ST values (adjusted for high diversity of markers) were 0.14–0.15. Slightly higher levels were observed between PNG populations and Solomon Islands (F ST = 0.16).Conclusions
Low levels of population structure despite geographical barriers to transmission are in sharp contrast to results from regions of low P. vivax endemicity. Prior to intensification of malaria control programs in the study area, parasite diversity and effective population size remained high. 相似文献84.
Kendall A. West Eckhard W. Heymann Britta Mueller Thomas R. Gillespie 《International journal of primatology》2013,34(5):939-945
Recent evidence of pathogen transmission to humans from wild primates and a greater recognition of the risk of human pathogen transmission to free-ranging primates have raised awareness of the potential impact of zoonotic pathogen transmission on primate conservation and nonhuman primate and human health. Cryptosporidium and Giardia are zoonotic protozoan parasites transmitted via fecal–oral contamination or water that can cause gastritis or enteritis in human and nonhuman primates. From June 2002 to September 2003, we collected fecal samples noninvasively from two species of tamarins (Saguinus mystax and S. nigrifrons) and one species of titi monkeys (Callicebus cupreus) at the Estación Biológica Quebrada Blanco in the Peruvian Amazon to determine the distribution and prevalence of these potential pathogens. We screened 140 fecal samples representing known individuals of each species for Cryptosporidium and Giardia using the Merifluor immunoflourescence assay to determine the prevalence and intensity of infection with these organisms. With the exception of two samples we collected during the same week from a juvenile male Saguinus mystax, all samples were negative for Cryptosporidium. None of the fecal samples were positive for Giardia. The low prevalence of infection we observed limited our ability to examine the effects of demographic and environmental variables on patterns of infection; however, the exceptionally low prevalence of Cryptosporidium suggests that it is not a current health threat to these primate populations. Although the origin of infection with Cryptosporidium in the juvenile male Saguinus mystax cannot be determined, its presence alerts us to the potential for cross-species transmission and highlights the need for more detailed research to improve our understanding of the distribution and diversity of potentially pathogenic protozoa in Neotropical primate populations. 相似文献
85.
Effect of light exposure on in vitro germination and germ tube growth of eight species of rust fungi
The effects of light on urediniospore germination and germ tube elongation was studied with eight species of rust fungi that infect ornamental plants or row crops. Exposure of six species of fungi to cool white fluorescent light at 400 or 600 micromol s(-1) m(-2) for 24 h significantly reduced germination with largest decreases typically observed at 600 micromol s(-1) m(-2). Germination and germ tube elongation did not recover during 24 h dark incubation after 18 h exposure to fluorescent light at 600 micromol s(-1) m(-2), indicating the effects were not reversible. Germ tube elongation of all fungi was negatively affected by increased length of exposure to fluorescent light. Increased exposure to fluorescent light differentially affected germination of the fungi with Puccinia hemerocallidis, Phakopsora pachyrhizi, Pucciniastrum vaccinii and Puccinia menthae negatively affected and Puccinia sorghi, Puccinia triticina, Puccinia pelargonii-zonalis and Puccinia iridis relatively unaffected in 10 h incubation. Exposure of Ph. pachyrhizi and P. triticina urediniospores to sunlight rapidly reduced germination and germ tube elongation with no germination observed for Ph. pachyrhizi after 2.5 h. Germ tube elongation but not germination of hydrated urediniospores of Ph. pachyrhizi and P. triticina was significantly reduced compared to dry urediniospores exposed to 10 h fluorescent light followed by 24 h dark incubation. Exposure to fluorescent light (all fungi) or sunlight (two fungi) negatively affected urediniospore germ tube elongation. Differences observed in urediniospore germination between fungi suggest some species have co-evolved with their host for differing light conditions. Our data suggests exposure of urediniospores to strong light could inactivate rust fungi on plant surfaces or in the atmosphere. 相似文献
86.
Hata K Fujitani M Yasuda Y Doya H Saito T Yamagishi S Mueller BK Yamashita T 《The Journal of cell biology》2006,173(1):47-58
Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA-Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration. 相似文献
87.
Keith L. Constantine Mark S. Friedrichs David Detlefsen Maki Nishio Mitsuaki Tsunakawa Tamotsu Furumai Hiroaki Ohkuma Toshikazu Oki Susan Hill Robert E. Bruccoleri Pin-Fang Lin Luciano Mueller 《Journal of biomolecular NMR》1995,5(3):271-286
Summary The 21-amino acid peptides siamycin II (BMY-29303) and siamycin I (BMY-29304), derived from Streptomyces strains AA3891 and AA6532, respectively, have been found to inhibit HIV-1 fusion and viral replication in cell culture. The primary sequence of siamycin II is CLGIGSCNDFAGCGYAIVCFW. Siamycin I differs by only one amino acid; it has a valine residue at position 4. In both peptides, disulfide bonds link Cys1 with Cys13 and Cys7 with Cys19, and the side chain of Asp9 forms an amide bond with the N-terminus. Siamycin II, when dissolved in a 50:50 mixture of DMSO and H2O, yields NOESY spectra with exceptional numbers of cross peaks for a peptide of this size. We have used 335 NOE distance constraints and 13 dihedral angle constraints to generate an ensemble of 30 siamycin II structures; these have average backbone atom and all heavy atom rmsd values to the mean coordinates of 0.24 and 0.52 Å, respectively. The peptide displays an unusual wedge-shaped structure, with one face being predominantly hydrophobic and the other being predominantly hydrophilic. Chemical shift and NOE data show that the siamycin I structure is essentially identical to siamycin II. These peptides may act by preventing oligomerization of the HIV transmembrane glycoprotein gp41, or by interfering with interactions between gp41 and the envelope glycoprotein gp120, the cell membrane or membrane-bound proteins [Frèchet, D. et al. (1994) Biochemistry, 33, 42–50]. The amphipathic nature of siamycin II and siamycin I suggests that a polar (or apolar) site on the target protein may be masked by the apolar (or polar) face of the peptide upon peptide/protein complexation.Abbreviations ABNR
adopted basis Newton Raphson
- AIDS
acquired immunodeficiency syndrome
- CW
continuous wave
- DMSO
dimethylsulfoxide
- DQF-COSY
two-dimensional double-quantum-filtered correlation spectroscopy
- HIV
human immunodeficiency virus
- HSQC
heteronuclear single-quantum coherence
- NOE
nuclear Overhauser enhancement
- NOESY
two-dimensional nuclear Overhauser enhancement spectroscopy
- ppm
parts per million
- P.E.-COSY
two-dimensional primitive exclusive correlation spectroscopy
- REDAC
redundant dihedral angle constraint
- rf
radio frequency
- rmsd
root-mean-square difference
- SIV
simian immunodeficiency virus
- sw
spectral width
- m
mixing time
- TOCSY
two-dimensional total correlation spectroscopy
- TSP
trimethylsilyl-2,2,3,3-2H4-propionate
- 2D
two-dimensional 相似文献
88.
Discovery and structural characterization of an allosteric inhibitor of bacterial cis‐prenyltransferase 下载免费PDF全文
Dennis E. Danley Eric T. Baima Mahmoud Mansour Kimberly F. Fennell Boris A. Chrunyk John P. Mueller Shenping Liu Xiayang Qiu 《Protein science : a publication of the Protein Society》2015,24(1):20-26
Undecaprenyl pyrophosphate synthase (UPPs) is an essential enzyme in a key bacterial cell wall synthesis pathway. It catalyzes the consecutive condensations of isopentenyl pyrophosphate (IPP) groups on to a trans-farnesyl pyrophosphate (FPP) to produce a C55 isoprenoid, undecaprenyl pyrophosphate (UPP). Here we report the discovery and co-crystal structures of a drug-like UPPs inhibitor in complex with Streptococcus pneumoniae UPPs, with and without substrate FPP, at resolutions of 2.2 and 2.1 Å, respectively. The UPPs inhibitor has a low molecular weight (355 Da), but displays potent inhibition of UPP synthesis in vitro (IC50 50 nM) that translates into excellent whole cell antimicrobial activity against pathogenic strains of Streptococcal species (MIC90 0.4 µg mL−1). Interestingly, the inhibitor does not compete with the substrates but rather binds at a site adjacent to the FPP binding site and interacts with the tail of the substrate. Based on the structures, an allosteric inhibition mechanism of UPPs is proposed for this inhibitor. This inhibition mechanism is supported by biochemical and biophysical experiments, and provides a basis for the development of novel antibiotics targeting Streptococcus pneumoniae. 相似文献
89.
Michela Menegon Azucena Bardají Flor Martínez-Espinosa Camila B?tto-Menezes Maria Ome-Kaius Ivo Mueller Inoni Betuela Myriam Arévalo-Herrera Swati Kochar Sanjay K. Kochar Puneet Jaju Dhiraj Hans Chetan Chitnis Norma Padilla María Eugenia Castellanos Lucía Ortiz Sergi Sanz Mireia Piqueras Meghna Desai Alfredo Mayor Hernando del Portillo Clara Menéndez Carlo Severini 《PloS one》2016,11(3)
Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied. 相似文献
90.
Large amounts of labile organic carbon in permafrost soils of northern Alaska 总被引:1,自引:0,他引:1 下载免费PDF全文
Carsten W. Mueller Janet Rethemeyer Jenny Kao‐Kniffin Sebastian Löppmann Kenneth M. Hinkel James G. Bockheim 《Global Change Biology》2015,21(7):2804-2817
Permafrost‐affected soils of the northern circumpolar region represent 50% of the terrestrial soil organic carbon (SOC) reservoir and are most strongly affected by climatic change. There is growing concern that this vast SOC pool could transition from a net C sink to a source. But so far little is known on how the organic matter (OM) in permafrost soils will respond in a warming future, which is governed by OM composition and possible stabilization mechanisms. To investigate if and how SOC in the active layer and adjacent permafrost is protected against degradation, we employed density fractionation to separate differently stabilized SOM fractions. We studied the quantity and quality of OM in different compartments using elemental analysis, 13C solid‐phase nuclear magnetic resonance (13C‐NMR) spectroscopy, and 14C analyses. The soil samples were derived from 16 cores from drained thaw lake basins, ranging from 0 to 5500 years of age, representing a unique series of developing Arctic soils over time. The normalized SOC stocks ranged between 35.5 and 86.2 kg SOC m?3, with the major amount of SOC located in the active layers. The SOC stock is dominated by large amounts of particulate organic matter (POM), whereas mineral‐associated OM especially in older soils is of minor importance on a mass basis. We show that tremendous amounts of over 25 kg OC per square meter are stored as presumably easily degradable OM rich in carbohydrates. Only about 10 kg OC per square meter is present as presumably more stable, mineral‐associated OC. Significant amounts of the easily degradable, carbohydrate‐rich OM are preserved in the yet permanently frozen soil below the permafrost table. Forced by global warming, this vast labile OM pool could soon become available for microbial degradation due to the continuous deepening of the annually thawing active layer. 相似文献