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841.
Loh J Popkin DL Droit L Braaten DC Zhao G Zhang X Vachharajani P Myers N Hansen TH Virgin HW 《Journal of virology》2012,86(5):2887-2893
Herpesviruses are thought to be highly genetically stable, and their use as vaccine vectors has been proposed. However, studies of the human gammaherpesvirus, Epstein-Barr virus, have found viral isolates containing mutations in HLA class I-restricted epitopes. Using murine gammaherpesvirus 68 expressing ovalbumin (OVA), we examined the stability of a gammaherpesvirus antigenic locus under strong CD8 T cell selection in vivo. OVA-specific CD8 T cells selected viral isolates containing mutations in the OVA locus but minimal alterations in other genomic regions. Thus, a CD8 T cell response to a gammaherpesvirus-expressed antigen that is not essential for replication or pathogenesis can result in selective mutation of that antigen in vivo. This finding may have relevance for the use of herpesvirus vectors for chronic antigen expression in vivo. 相似文献
842.
843.
Loh XJ del Barrio J Toh PP Lee TC Jiao D Rauwald U Appel EA Scherman OA 《Biomacromolecules》2012,13(1):84-91
The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers. 相似文献
844.
Sicinschi LA Correa P Bravo LE Peek RM Wilson KT Loh JT Yepez MC Gold BD Thompson DT Cover TL Schneider BG 《Helicobacter》2012,17(2):96-106
Background: Helicobacter pylori infection is usually acquired in childhood, but little is known about its natural history in asymptomatic children, primarily due to the paucity of non‐invasive diagnostic methods. H. pylori strains harboring cagA and specific alleles of hopQ and vacA are associated with increased risk for gastric cancer. Many studies of H. pylori virulence markers in children have the bias that symptomatic subjects are selected for endoscopy, and these children may harbor the most virulent strains. Our aim is to genotype cagA, hopQ, and vacA alleles in stool DNA samples of healthy Colombian children residing in an area with high incidence of gastric cancer, to avoid selection bias resulting from endoscopy. Methods: H. pylori status of 86 asymptomatic children was assessed by 13C‐urea breath test (UBT) and PCR. H. pylori 16S rRNA, cagA, hopQ, and vacA genes were amplified from stool DNA samples and sequenced. Results: UBT was positive in 69 (80.2%) of 86 children; in stool DNA analysis, 78.3% were positive by 16S rRNA PCR. cagA, vacA, and hopQ were detected in 66.1%, 84.6%, and 72.3% of stool DNA samples from 16S rRNA‐positive children. Of the children’s DNA samples, which revealed vacA and hopQ alleles, 91.7% showed vacA s1 and 73.7% showed type I hopQ. Type I hopQ alleles were associated with cagA positivity and vacA s1 genotypes (p < 0.0001). Conclusions: Using stool DNA samples, virulence markers of H. pylori were successfully genotyped in a high percentage of the asymptomatic infected children, revealing a high prevalence of genotypes associated with virulence. Type I hopQ alleles were associated with the presence of cagA and the vacA s1 genotype. 相似文献
845.
Sian E. Piret Christopher T. Esapa Caroline M. Gorvin Rosie Head Nellie Y. Loh Olivier Devuyst Gethin Thomas Steve D. M. Brown Matthew Brown Peter Croucher Roger Cox Rajesh V. Thakker 《PloS one》2012,7(9)
Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. 相似文献
846.
Wiede F Chew SH van Vliet C Poulton IJ Kyparissoudis K Sasmono T Loh K Tremblay ML Godfrey DI Sims NA Tiganis T 《PloS one》2012,7(5):e36703
Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2(ex2-/ex2-) mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2(-/-) mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2(ex2-/ex2-) mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2(-/-) (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2(-/-) (BALB/c) mice were not detected in Ptpn2(ex2-/ex2-) mice. At 14 days of age, bone development was delayed in Ptpn2(-/-) (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2(ex2-/ex2-) mice. Ptpn2(ex2-/ex2-) mice had defects in erythropoiesis and B cell development as evident in Ptpn2(-/-) (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2(-/-) (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2(-/-) (BALB/c) mice, was delayed in Ptpn2(ex2-/ex2-) mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2(-/-) (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2(ex2-/ex2-) mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent. 相似文献
847.
Gene delivery into cells to elicit cellular response has received a great attention recently. Viruses, lipids, peptides, cationic polymers and certain inorganic nanomaterials have been reported as gene delivery vectors. In this review, we focus on the recent literature on gene delivery using inorganic nanoparticles. This emerging field of study is concisely summarized and illustrated by selected examples and recent patents. New approaches and directions towards the practical use of multifunctional nanocarriers are highlighted. 相似文献
848.
849.
Background
Accumulating evidence indicates aberrant DNA methylation is involved in gastric tumourigenesis, suggesting it may be a useful clinical biomarker for the disease. The aim of this study was to consolidate and summarize published data on the potential of methylation in gastric cancer (GC) risk prediction, prognostication and prediction of treatment response.Methods
Relevant studies were identified from PubMed using a systematic search approach. Results were summarized by meta-analysis. Mantel-Haenszel odds ratios were computed for each methylation event assuming the random-effects model.Results
A review of 589 retrieved publications identified 415 relevant articles, including 143 case-control studies on gene methylation of 142 individual genes in GC clinical samples. A total of 77 genes were significantly differentially methylated between tumour and normal gastric tissue from GC subjects, of which data on 62 was derived from single studies. Methylation of 15, 4 and 7 genes in normal gastric tissue, plasma and serum respectively was significantly different in frequency between GC and non-cancer subjects. A prognostic significance was reported for 18 genes and predictive significance was reported for p16 methylation, although many inconsistent findings were also observed. No bias due to assay, use of fixed tissue or CpG sites analysed was detected, however a slight bias towards publication of positive findings was observed.Conclusions
DNA methylation is a promising biomarker for GC risk prediction and prognostication. Further focused validation of candidate methylation markers in independent cohorts is required to develop its clinical potential. 相似文献850.
De Los Angeles A Loh YH Tesar PJ Daley GQ 《Current opinion in genetics & development》2012,22(3):272-282
Pluripotency manifests during mammalian development through formation of the epiblast, founder tissue of the embryo proper. Rodent pluripotent stem cells can be considered as two distinct states: na?ve and primed. Na?ve pluripotent stem cell lines are distinguished from primed cells by self-renewal in response to LIF signaling and MEK/GSK3 inhibition (LIF/2i conditions) and two active X chromosomes in female cells. In rodent cells, the na?ve pluripotent state may be accessed through at least three routes: explantation of the inner cell mass, somatic cell reprogramming by ectopic Oct4, Sox2, Klf4, and C-myc, and direct reversion of primed post-implantation-associated epiblast stem cells (EpiSCs). In contrast to their rodent counterparts, human embryonic stem cells and induced pluripotent stem cells more closely resemble rodent primed EpiSCs. A critical question is whether na?ve human pluripotent stem cells with bona fide features of both a pluripotent state and na?ve-specific features can be obtained. In this review, we outline current understanding of the differences between these pluripotent states in mice, new perspectives on the origins of na?ve pluripotency in rodents, and recent attempts to apply the rodent paradigm to capture na?ve pluripotency in human cells. Unraveling how to stably induce na?ve pluripotency in human cells will influence the full realization of human pluripotent stem cell biology and medicine. 相似文献