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81.
Truc Thi Kim Thanh Hoang Anneline Nansen Sugata Roy Rolf Billeskov Claus Aagaard Tara Elvang Jes Dietrich Peter Andersen 《PloS one》2009,4(6)
Background
Recently we and others have identified CD8 and CD4 T cell epitopes within the highly expressed M. tuberculosis protein TB10.4. This has enabled, for the first time, a comparative study of the dynamics and function of CD4 and CD8 T cells specific for epitopes within the same protein in various stages of TB infection.Methods and Findings
We focused on T cells directed to two epitopes in TB10.4; the MHC class I restricted epitope TB10.4 3–11 (CD8/10.4 T cells) and the MHC class II restricted epitope TB10.4 74–88 (CD4/10.4 T cells). CD4/10.4 and CD8/10.4 T cells displayed marked differences in terms of expansion and contraction in a mouse TB model. CD4/10.4 T cells dominated in the early phase of infection whereas CD8/10.4 T cells were expanded after week 16 and reached 5–8 fold higher numbers in the late phase of infection. In the early phase of infection both CD4/10.4 and CD8/10.4 T cells were characterized by 20–25% polyfunctional cells (IL-2+, IFN-γ+, TNF-α+), but whereas the majority of CD4/10.4 T cells were maintained as polyfunctional T cells throughout infection, CD8/10.4 T cells differentiated almost exclusively into effector cells (IFN-γ+, TNF-α+). Both CD4/10.4 and CD8/10.4 T cells exhibited cytotoxicity in vivo in the early phase of infection, but whereas CD4/10.4 cell mediated cytotoxicity waned during the infection, CD8/10.4 T cells exhibited increasing cytotoxic potential throughout the infection.Conclusions/Significance
Our results show that CD4 and CD8 T cells directed to epitopes in the same antigen differ both in their kinetics and functional characteristics throughout an infection with M. tuberculosis. In addition, the observed strong expansion of CD8 T cells in the late stages of infection could have implications for the development of post exposure vaccines against latent TB. 相似文献82.
Heiman F. L. Wertheim Huyen Nguyen Nguyen Walter Taylor Trinh Thi Minh Lien Hoa Thi Ngo Thai Quoc Nguyen Bich Ngoc Thi Nguyen Ha Hong Nguyen Ha Minh Nguyen Cap Trung Nguyen Trinh Tuyet Dao Trung Vu Nguyen Annette Fox Jeremy Farrar Constance Schultsz Hien Duc Nguyen Kinh Van Nguyen Peter Horby 《PloS one》2009,4(6)
Background
Streptococcus suis can cause severe systemic infection in adults exposed to infected pigs or after consumption of undercooked pig products. S. suis is often misdiagnosed, due to lack of awareness and improper testing. Here we report the first fifty cases diagnosed with S. suis infection in northern Viet Nam.Methodology/Principal Findings
In 2007, diagnostics for S. suis were set up at a national hospital in Hanoi. That year there were 43 S. suis positive cerebrospinal fluid samples, of which S. suis could be cultured in 32 cases and 11 cases were only positive by PCR. Seven patients were blood culture positive for S. suis but CSF culture and PCR negative; making a total of 50 patients with laboratory confirmed S. suis infection in 2007. The number of S. suis cases peaked during the warmer months.Conclusions/Significance
S. suis was commonly diagnosed as a cause of bacterial meningitis in adults in northern Viet Nam. In countries where there is intense and widespread exposure of humans to pigs, S. suis can be an important human pathogen. 相似文献83.
Palmitoyl Protein Thioesterase 1 (PPT1) is an essential lysosomal protein in the mammalian nervous system whereby defects result in a fatal pediatric disease called Infantile Neuronal Ceroids Lipofuscinosis (INCL). Flies bearing mutations in the Drosophila ortholog Ppt1 exhibit phenotypes similar to the human disease: accumulation of autofluorescence deposits and shortened adult lifespan. Since INCL patients die as young children, early developmental neural defects due to the loss of PPT1 are postulated but have yet to be elucidated. Here we show that Drosophila Ppt1 is required during embryonic neural development. Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord. Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections. These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation. Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila. These findings may be relevant for understanding the developmental origin of neural deficiencies in INCL. 相似文献
84.
85.
Berberine exerts an anti-adipogenic activity that is associated with the down-regulation of C/EBPα and PPARγ. Stimulation of AMP-activated kinase (AMPK) caused by inhibition of mitochondrial respiration has been suggested to underlie such molecular regulation. In the present study, we show that berberine up-regulated the expression of two different sets of C/EBP inhibitors, CHOP and DEC2, while down-modulating C/EBPα, PPARγ and other adipogenic markers and effectors in differentiating 3T3-L1 preadipocytes and mature adipocytes. Data also suggested that the berberine-induced up-regulation of CHOP and DEC2 was attributable to selective activation of an unfolded protein response (UPR) and modified extracellular environment, respectively. As a result, the anti-adipogenic activity of berberine was diminished remarkably by adjusting the differentiation culture media and limitedly but consistently by knockdown of CHOP expression. Together, up-regulation of C/EBP inhibitors appears to underlie the berberine-induced repression of C/EBPα and PPARγ and, so, the inhibition of adipogenesis. 相似文献
86.
In the Parkinson's disease-associated state, α-synuclein undergoes large conformational changes, forming ordered, β-sheet-containing fibrils. To unravel the role of specific residues during the fibril assembly process, we prepared single-Cys mutants in the disordered (G7C and Y136C) and proximal (V26C and L100C) fibril core sites and derivatized them with environmentally sensitive dansyl (Dns) fluorophores. Dns fluorescence exhibits residue specificity in spectroscopic properties as well as kinetic behavior; early kinetic events were revealed by probes located at positions 7 and 136 compared to those at positions 26 and 100. 相似文献
87.
Tran QT Nawaz MS Deck J Nguyen KT Cerniglia CE 《Applied and environmental microbiology》2011,77(5):1885-1887
Fourteen quinolone-resistant Pseudomonas putida isolates were recovered from imported frozen shrimp sold in the United States. Two isolates harbored plasmids with qnrA and qnrB genes. PCR and DNA sequencing of quinolone resistance-determining regions identified novel substitutions in GyrA (His139→Glu and Thr128→Ala) and GyrB (Thr442→Asn, Gly470→Ala, and Ile487→Pro) and previously reported substitutions in GyrB (Asp489→Glu) and ParC (Thr105→Pro). 相似文献
88.
Balog ER Saetern OC Finch W Hoeft CO Thai V Harvey SL Kellogg DR Rubin SM 《Journal of molecular biology》2011,411(3):520-528
Cks (cyclin-dependent kinase subunit) proteins are essential eukaryotic cell cycle regulatory proteins that physically associate with cyclin-dependent kinases (Cdks) to modulate their activity. Cks proteins have also been studied for their ability to form domain-swapped dimers by exchanging β-strands. Domain swapping is mediated by a conserved β-hinge region containing two proline residues. Previous structural studies indicate that Cks in its dimer form is unable to bind Cdk, suggesting that the monomer-dimer equilibrium of Cks may have an effect on Cks-mediated Cdk regulation. We present the crystal structure of a proline-to-alanine mutant Saccharomyces cerevisiae Cks protein (Cks1 P93A) that preferentially adopts the monomer conformation but surprisingly fails to bind Cdk. Comparison of the Cks1 P93A structure to that of other Cks proteins reveals that Pro93 is critical for stabilizing a multiple β-turn structure in the hinge region that properly positions an essential Cdk-binding residue. Additionally, we find that these β-turn formations, conserved in Cks homologs, have implications for the mechanism and preferentiality of strand exchange. Together, our observations suggest that the conservation of Cks hinge-region prolines reflects their functions in forming a Cdk binding interface and that the ability of these prolines to control partitioning between monomer and dimer is a consequence of the β-turn networks within the hinge. 相似文献
89.
Nguyen GK Zhang S Wang W Wong CT Nguyen NT Tam JP 《The Journal of biological chemistry》2011,286(52):44833-44844
Cyclotides are heat-stable macrocyclic peptides from plants that display a wide range of biological activities. They can be divided into two subfamilies: Möbius or bracelet, based on the presence or absence of a cis-proline residue in loop 5, respectively. Currently, over 150 cyclotides have been discovered, but only four linear variants of the Möbius subfamily have been hitherto isolated. In this study, we report the discovery of two novel cyclotides, hedyotide B1 and hedyotide B2, from the aerial parts of Hedyotis biflora. Hedyotide B1 has a cyclic cystine knot structure typical of cyclotides. Interestingly, hedyotide B2 possesses a linear backbone and is the first linear representative of the bracelet subfamily. Disulfide mapping of hedyotide B2 by a top-down MS/MS approach showed that it shares the same knotted disulfide arrangement as conventional cyclotides. Its unfolding pathway also showed that the penetrating disulfide bond Cys III–VI is the most stable disulfide linkage. Cloning of the gene encoding hedyotide B2 revealed a nonsense mutation that introduces a premature stop codon at the conserved Asn residue position, which is essential for an end-to-end backbone ligation. Biophysical characterization showed that hedyotide B2 was more susceptible to exopeptidase degradation as compared with hedyotide B1. Hedyotide B2 was also inactive against all four tested bacterial strains, whereas hedyotide B1 was bactericidal to Escherichia coli and Streptococcus salivarius at low micromolar concentration. Our results provide a deeper understanding of the structures, functions, and biosynthetic processing of cyclotides and uncyclotides in plants. 相似文献
90.