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91.
Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies 下载免费PDF全文
Maike F. Dohrn Nicola Glöckle Lejla Mulahasanovic Corina Heller Julia Mohr Christine Bauer Erik Riesch Andrea Becker Florian Battke Konstanze Hörtnagel Thorsten Hornemann Saranya Suriyanarayanan Markus Blankenburg Jörg B. Schulz Kristl G. Claeys Burkhard Gess Istvan Katona Andreas Ferbert Debora Vittore Alexander Grimm Stefan Wolking Ludger Schöls Holger Lerche G. Christoph Korenke Dirk Fischer Bertold Schrank Urania Kotzaeridou Gerhard Kurlemann Bianca Dräger Anja Schirmacher Peter Young Beate Schlotter‐Weigel Saskia Biskup 《Journal of neurochemistry》2017,143(5):507-522
92.
Khairul A. Kamaruzaman Peter M. Moyle Istvan Toth 《International journal of peptide research and therapeutics》2017,23(1):119-134
Gene therapy is a promising means to treat or prevent diseases either through gene silencing or expression. Some of the most effective delivery agents are polycationic dendrimers, which are highly branched constructs incorporating many positively charged groups. Two of the most effective dendrimers are polyethyleneimine (PEI) and poly(amidoamine) (PAMAM), which show high proficiency at overcoming barriers to oligonucleotide delivery. However, because of their abundance of cationic charge, they are associated with severe toxicity. We have therefore aimed to develop a low toxicity oligonucleotide delivery system, incorporating multiple components that have been selected and optimised to overcome the barriers to efficient oligonucleotide delivery. In this work we have focused on improving the toxicity, cellular uptake, and condensation of plasmid DNA (pDNA) through the fusion of synthetic poly-l-lysine (PLL) dendrons with the cell penetrating peptide TAT(48-60). A library of dendron structures, from 4+ to 16+ charge, and constructs containing six histidine residues, were synthesised. The effects of each modification on pDNA binding and condensation; cellular uptake and toxicity; and the size and zeta-potential of the complexes were assessed to identify the optimum dendron for incorporation into our systems. This work concluded that increasing the dendron charge from 4+ to 16+ significantly improved cellular uptake and pDNA condensation, with no effect on toxicity, while PLL dendrons with greater than 16+ charge could not be efficiently produced. In comparison, the incorporation of six histidines into these constructs had a variable effect on cellular uptake, and generated larger sized complexes, but did not affect toxicity. 相似文献
93.
MOTIVATION: High-throughput 'ChIP-chip' and 'ChIP-seq' methodologies generate sufficiently large data sets that analysis poses significant informatics challenges, particularly for research groups with modest computational support. To address this challenge, we devised a software platform for storing, analyzing and visualizing high resolution genome-wide binding data. GeneTrack automates several steps of a typical data processing pipeline, including smoothing and peak detection, and facilitates dissemination of the results via the web. Our software is freely available via the Google Project Hosting environment at http://genetrack.googlecode.com 相似文献
94.
The opioid receptor system in the central nervous system controls a number of physiological processes, most notably pain. However, most opioids currently available have a variety of side-effects as well as exhibiting tolerance. Tolerance is most likely to be a complex phenomenon, however, the role of receptor internalisation is thought to play a crucial role. In this study, we examined the role of aromaticity in ligand-mediated receptor internalisation of the mu-opioid receptor (MOPR). These studies show that the amount of receptor internalisation may be dependant on the amphiphilicity of the ligand. Specifically, deletion of the C-terminus aromatic residues of endomorphin 1, particularly tryptophan reduces receptor-mediated internalisation whilst the addition of tryptophan within the enkephalin sequence increases receptor internalisation and decreases tolerance. 相似文献
95.
Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein 总被引:1,自引:0,他引:1
Gurusamy N Lekli I Gorbunov NV Gherghiceanu M Popescu LM Das DK 《Journal of cellular and molecular medicine》2009,13(2):373-387
Autophagy is an intracellular process in which a cell digests its own constituents via lysosomal degradative pathway. Though autophagy has been shown in several cardiac diseases like heart failure, hypertrophy and ischaemic cardiomyopathy, the role and the regulation of autophagy is still largely unknown. Bcl-2-associated athanogene (BAG-1) is a multifunctional pro-survival molecule that binds with Hsp70/Hsc70. In this study, myocardial adaptation to ischaemia by repeated brief episodes of ischaemia and reperfusion (I/R) prior to lethal I/R enhanced the expression of autophagosomal membrane specific protein light chain 3 (LC3)-II, and Beclin-1, a molecule involved in autophagy and BAG-1. Autophagosomes structures were found in the adapted myocardium through electron microscopy. Co-immunoprecipitation and co-immunofluorescence analyses revealed that LC3-II was bound with BAG-1. Inhibition of autophagy by treating rats with Wortmannin (15 μg/kg; intraperitoneally) abolished the ischaemic adaptation-induced induction of LC3-II, Beclin-1, BAG-1 and cardioprotection. Intramyocardial injection of BAG-1 siRNA attenuated the induction of LC3-II, and abolished the cardioprotection achieved by adaptation. Furthermore, hypoxic adaptation in cardiac myoblast cells induced LC3-II and BAG-1. BAG-1 siRNA treatment attenuated hypoxic adaptation-induced LC3-II and BAG-1, and abolished improvement in cardiac cell survival and reduction of cell death. These results clearly indicate that myocardial protection elicited by adaptation is mediated at least in part via up-regulation of autophagy in association with BAG-1 protein. 相似文献
96.
Nilesh Dharajiya Swapnil Vaidya Mala Sinha Bruce Luxon Istvan Boldogh Sanjiv Sur 《PloS one》2009,4(12)
According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatory genes to counter-balance the effects of Th2 cytokines and chemokines. To identify these putative anti-inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1-associated genes remain upregulated longer than the Th2 genes. Augmentation of the local Th1 milieu by administration of Il12 or CpG prior to RWE challenge further upregulated these Th1 genes. Abolition of the Th1 response by disrupting the Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10 and Socs1, but not Gadd45g. Our data demonstrate that allergen challenge induces two sets of Th1-associated genes in the lungs: 1) Ifng-dependent genes such as p47 and p65 GTPases, Socs1, Cxcl9 and Cxcl10 and 2) Ifng-independent Th1-inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulation of Th1 and Th2 genes, and that persistent unopposed upregulation of Th1 genes resolves allergic inflammation. 相似文献
97.
Szatmari I Vámosi G Brazda P Balint BL Benko S Széles L Jeney V Ozvegy-Laczka C Szántó A Barta E Balla J Sarkadi B Nagy L 《The Journal of biological chemistry》2006,281(33):23812-23823
98.
Presence of Anti-Microbial Antibodies in Liver Cirrhosis – A Tell-Tale Sign of Compromised Immunity?
Papp M Norman GL Vitalis Z Tornai I Altorjay I Foldi I Udvardy M Shums Z Dinya T Orosz P Lombay B Par G Par A Veres G Csak T Osztovits J Szalay F Lakatos PL 《PloS one》2010,5(9):e12957
Background
Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn''s disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections.Methodology/Principal Findings
Sera of 676 patients with various chronic liver diseases (autoimmune diseases:266, viral hepatitis C:124, and liver cirrhosis of different etiology:286) and 100 controls were assayed for antibodies to Saccharomyces cerevisiae(ASCA) and to antigens derived from two intestinal bacterial isolates (one gram positive, one gram negative, neither is Escherichia coli). In patients with liver cirrhosis, we also prospectively recorded the development of severe episodes of bacterial infection. ASCA and anti-OMP Plus™ antibodies were present in 38.5% and 62.6% of patients with cirrhosis and in 16% and 20% of controls, respectively (p<0.001). Occurrence of these antibodies was more frequent in cases of advanced cirrhosis (according to Child-Pugh and MELD score; p<0.001) or in the presence of ascites (p<0.001). During the median follow-up of 425 days, 81 patients (28.3%) presented with severe bacterial infections. Anti-microbial antibody titers (p = 0.003), as well as multiple seroreactivity (p = 0.036), was associated with infectious events. In logistic regression analysis, the presence of ascites (OR:1.62, 95%CI:1.16–2.25), co-morbidities (OR:2.22, 95%CI:1.27–3.86), and ASCA positivity (OR:1.59, 95%CI:1.07–2.36) were independent risk factors for severe infections. A shorter time period until the first infection was associated with the presence of ASCA (p = 0.03) and multiple seropositivity (p = 0.037) by Kaplan-Meier analysis, and with Child-Pugh stage (p = 0.018, OR:1.85) and co-morbidities (p<0.001, OR:2.02) by Cox-regression analysis.Conclusions/Significance
The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies. 相似文献99.
100.
Christopher M. Grainger Istvan Rajcan 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2014,127(1):211-229
Genotyping through the pedigrees of elite soybean [Glycine max (L.) Merr.] cultivars developed by a breeding program represents an opportunity to explore and characterize various molecular and genetic changes that are a direct result of long-term selection by soybean breeders. For soybeans bred for Ontario Canada, one such elite cultivar was OAC Bayfield, which had exceptional commercial success as well as being a parent of a number of successful cultivars developed by multiple independent breeding programs. A total of 42 genotypes from six different breeding programs, comprising the multi-generational pedigree of OAC Bayfield were genotyped with molecular markers and chromosomal inheritance was tracked throughout the pedigree. Cluster analysis showed high congruence with the known pedigree and identified three distinct ancestral groups. The ancestral genotypes contained the majority of the rare alleles, with the cultivar CNS having the greatest number of unique alleles. The graphical genotype profile for the 20 chromosomes revealed conserved allelic composition which has been assembled in certain chromosomes in the form of specific linkage blocks, which were either a result of recombination involving ancestral linkage blocks or linkage blocks introduced from the cultivar Fiskeby-V. The identification of highly structured, conserved genomic regions are important for future breeding efforts as they are indicators of preferentially selected regions, or conversely, may be a contributing factor to low genetic gains due to mass fixation across a breeding program’s germplasm. 相似文献