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Search Results: 1 - 10 of 44802 matches for " Krawczak Michael "
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Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques
Roman A. Siddiqui, Michael Krawczak, Matthias Platzer, Ulrike Sauermann
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025474
Abstract: In HIV infection, TLR7-triggered IFN-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP) as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i) that SNP c.13G>A in the leader peptide is causative for the observed genotype-phenotype association and that (ii) the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C>T), located 17 bp upstream of the ATG translation initiation codon, that is also potentially capable of influencing RNA structure. In c.13A carriers, neither set-point viral load nor survival time were related to the c.-17C>T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantly associated with prolonged survival. Again, no such association was detected among immunized SIV-infected macaques. Our results highlight the dual role of TLR7 in immunodeficiency virus infection and vaccination and imply that it may be important to control human AIDS vaccine trials, not only for MHC genotype, but also for TLR7 genotype.
Is the NIH policy for sharing GWAS data running the risk of being counterproductive?
Michael Krawczak, Jürgen W Goebel, David N Cooper
Investigative Genetics , 2010, DOI: 10.1186/2041-2223-1-3
Abstract: In January 2008, the US National Institutes of Health (NIH) put into effect their Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS) (NOT-OD-07-088) [1]. The self-declared goal of this policy was 'to advance science for the benefit of the public through the creation of a centralized NIH GWAS data repository' (NOT-OD-07-088) [1]. The policy, which was revised and expanded in October 2009 so as to include DNA sequence data (NOT-HG-10-006) [2], was inspired by the view espoused by the NIH 'that the full value of GWAS to the public can be realized only if the genotype and phenotype datasets are made available as rapidly as possible to a wide range of scientific investigators' (NOT-OD-07-088) [1]. Irrespective of whether this view is justified (for example, on the basis of previous experience or persuasive scientific evidence), its implementation in the context of public funding practice may well place a serious burden upon researchers performing GWAS or large-scale sequencing studies. This would appear to be particularly true with regard to those researchers who initiated and conducted their research projects outside of the NIH sphere of influence, and who have only latterly come under its aegis by virtue of their being involved in collaborations with at least one NIH-funded partner. Although the NIH initiated a public consultation process in 2006, no representations were taken from non-US sources, as far as we can see. This was a serious omission, because the lack of any centralized health service provider in the USA implies that US researchers might in time have to become at least partially dependent upon well-characterized patient cohorts from other countries.The major drawback of the current NIH policy is the mandatory requirement to place all genome-wide genotyping/nucleic acid sequence data (plus all relevant phenotypic information) from NIH-funded and NIH-supported studies into the NIH's own repository, the Da
‘Sifting the significance from the data’ - the impact of high-throughput genomic technologies on human genetics and health care
Clarke Angus J,Cooper David N,Krawczak Michael,Tyler-Smith Chris
Human Genomics , 2012, DOI: 10.1186/1479-7364-6-11
Abstract: This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK’s Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions.
Chromosomal evolution of the PKD1 gene family in primates
Stefan Kirsch, Juanjo Pasantes, Andreas Wolf, Nadia Bogdanova, Claudia Münch, Petra Pennekamp, Michael Krawczak, Bernd Dworniczak, Werner Schempp
BMC Evolutionary Biology , 2008, DOI: 10.1186/1471-2148-8-263
Abstract: Comparative FISH with the PKD1-cDNA clone clearly shows that in all primate species studied distinct single signals map in subtelomeric chromosomal positions orthologous to the short arm of human chromosome 16 harbouring the master PKD1 gene. Only in human and African great apes, but not in orangutan, FISH with both BAC and cDNA clones reveals additional signal clusters located proximal of and clearly separated from the PKD1 master genes indicating the chromosomal position of PKD1 pseudogenes in 16p of these species, respectively. Indeed, this is in accordance with sequencing data in human, chimpanzee and orangutan. Apart from the master PKD1 gene, six pseudogenes are identified in both, human and chimpanzee, while only a single-copy gene is present in the whole-genome sequence of orangutan. The phylogenetic reconstruction of the PKD1-tree reveals that all human pseudogenes are closely related to the human PKD1 gene, and all chimpanzee pseudogenes are closely related to the chimpanzee PKD1 gene. However, our statistical analyses provide strong indication that gene conversion events may have occurred within the PKD1 family members of human and chimpanzee, respectively.PKD1 must have undergone amplification very recently in hominid evolution. Duplicative transposition of the PKD1 gene and further amplification and evolution of the PKD1 pseudogenes may have arisen in a common ancestor of Homo, Pan and Gorilla ~8 MYA. Reticulate evolutionary processes such as gene conversion and non-allelic homologous recombination (NAHR) may have resulted in concerted evolution of PKD1 family members in human and chimpanzee and, thus, simulate an independent evolution of the PKD1 pseudogenes from their master PKD1 genes in human and chimpanzee.Autosomal dominant polycystic kidney disease (ADPKD) is a late onset systemic disorder characterised by the progressive development of multiple fluid filled cysts in the kidney, ultimately leading to renal failure [1]. Peters and Sandkuijl [2] es
Diagnosing Fatty Liver Disease: A Comparative Evaluation of Metabolic Markers, Phenotypes, Genotypes and Established Biomarkers
Sabine Siegert, Zhonghao Yu, Rui Wang-Sattler, Thomas Illig, Jerzy Adamski, Jochen Hampe, Susanna Nikolaus, Stefan Schreiber, Michael Krawczak, Michael Nothnagel, Ute N?thlings
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076813
Abstract: Background To date, liver biopsy is the only means of reliable diagnosis for fatty liver disease (FLD). Owing to the inevitable biopsy-associated health risks, however, the development of valid noninvasive diagnostic tools for FLD is well warranted. Aim We evaluated a particular metabolic profile with regard to its ability to diagnose FLD and compared its performance to that of established phenotypes, conventional biomarkers and disease-associated genotypes. Methods The study population comprised 115 patients with ultrasound-diagnosed FLD and 115 sex- and age-matched controls for whom the serum concentration was measured of 138 different metabolites, including acylcarnitines, amino acids, biogenic amines, hexose, phosphatidylcholines (PCs), lyso-PCs and sphingomyelins. Established phenotypes, biomarkers, disease-associated genotypes and metabolite data were included in diagnostic models for FLD using logistic regression and partial least-squares discriminant analysis. The discriminative power of the ensuing models was compared with respect to area under curve (AUC), integrated discrimination improvement (IDI) and by way of cross-validation (CV). Results Use of metabolic markers for predicting FLD showed the best performance among all considered types of markers, yielding an AUC of 0.8993. Additional information on phenotypes, conventional biomarkers or genotypes did not significantly improve this performance. Phospholipids and branched-chain amino acids were most informative for predicting FLD. Conclusion We show that the inclusion of metabolite data may substantially increase the power to diagnose FLD over that of models based solely upon phenotypes and conventional biomarkers.
Chromosomal evolution of the PKD1 gene family in primates
Stefan Kirsch, Juanjo Pasantes, Andreas Wolf, Nadia Bogdanova, Claudia Münch, Arseni Markoff, Petra Pennekamp, Michael Krawczak, Bernd Dworniczak, Werner Schempp
BMC Evolutionary Biology , 2009, DOI: 10.1186/1471-2148-9-14
Abstract: After publication of this work [1], we noted that we inadvertently failed to include the complete list of all co-authors. The full list of authors including Arseni Markoff has now been added.Stefan Kirsch, Juanjo Pasantes, Andreas Wolf, Nadia Bogdanova, Claudia Münch, Arseni Markoff, Petra Pennekamp, Michael Krawczak, Bernd Dworniczak and Werner SchemppSK performed parts of the molecular phylogenetic analyses and helped to finalize the manuscript, JP and CM performed the FISH experiments, AW and MK performed the statistical analyses and helped to finalize the corresponding sections of the manuscript, NB, AM and PP performed probe identification, preparation and characterization, BD and WS designed the study, and WS drafted and finalized the manuscript.
Association studies of the copy-number variable ?-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis
Stefan Taudien, Gabor G?bel, Oliver Kuss, Marco Groth, Robert Grützmann, Klaus Huse, Alexander Kluttig, Andreas Wolf, Michael Nothnagel, Philip Rosenstiel, Karin Halina Greiser, Karl Werdan, Michael Krawczak, Christian Pilarsky, Matthias Platzer
BMC Research Notes , 2012, DOI: 10.1186/1756-0500-5-629
Abstract: Two groups of PDAC (N=70) and CP (N=60) patients were compared to matched healthy control groups CARLA1 (N=232) and CARLA2 (N=160), respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification.Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively.The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher’s exact test P=0.027), but not between CP and CARLA2 (P=0.867).Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.Pancreatitis, a necroinflammatory condition of the pancreas, has both acute and chronic manifestations. In the recent past, our understanding of the pathogenesis of pancreatic inflammation has improved considerably. Whereas acute pancreatitis is known to be initiated by premature activation of digestive enzymes within the exocrine component of the pancreas, chronic pancreatitis (CP) is characterized by progressive and irreversible damage to both the exocrine and endocrine components of the pancreas. CP is believed to result from repeated overt or silent episodes of acute pancreatitis [1]. The key histopathologic features of CP are pancreatic fibrosis, acinar atrophy, chronic inflammation, and distorted and blocked ducts [2]. The annual incidence of CP in industrialized countries ranges from 3.5 to 10 per 100,000. Alcohol abuse is the major risk factor for CP in Western countries, although other mechanisms such as mutations, pancreatic duct obstruction (caused by strictures), hypertriglyceridemia, hypercalcemia, and autoimmunity also have been implicated [3]. Since patients with CP have an approximately 13-fold higher risk to develop pancreatic cancer than the general population, the ide
Fracture Mechanics Applied to the Analysis of the Degradation of Anti-Corrosion Glass / Resin Pipes As a Function of the Fibre / Matrix Interface Quality Application de la mécanique de la rupture à l'analyse de la dégradation de canalisations anti-corrosion verre / résine en fonction de la qualité de l'interface fibre / matrice
Krawczak P.,Benteyn M.,Pabiot J.
Oil & Gas Science and Technology , 2006, DOI: 10.2516/ogst:1995011
Abstract:
Development of novel melt-compounded starch-grafted polypropylene/polypropylene-grafted maleic anhydride/organoclay ternary hybrids
E. Lafranche,R. Tessier,P. Krawczak
eXPRESS Polymer Letters , 2012, DOI: 10.3144/expresspolymlett.2012.99
Abstract: Starch-grafted polypropylene (PP-g-starch)/organoclay nanocomposites were melt-compounded using a corotating twin-screw extruder. Homopolymer or copolymer-based polypropylene-grafted maleic anhydrides (PP-g-MA) with different molecular weights and different maleic anhydride (MA) grafting levels were added at different weight contents as compatibilizer. Two organo-modified montmorillonites were used, the first one containing polar functional groups (Cloisite 30B) having affinity to the starch phase, and the other one containing non polar-groups (Cloisite 20A) having affinity to the polypropylene phase of the polymer matrix. Whatever the MA grafting level and the molecular weight and content of PP-g-MA, no significant immiscibility of PP-g-starch/PP-g-MA blends is evidenced. Regarding clay dispersion, adding a low content of ethylene-propylene copolymer-based PP-g-MA compatibilizer having a high MA-grafting level, and a polar organoclay (Cloisite 30B) is the most desirable formulation to optimize clay intercalation and exfoliation in PP-g-starch. Nevertheless, regarding the reinforcement effect, whatever the PP-g-MA compatibilizer, the addition of non polar organoclay (Cloisite 20A) is preferably recommended to reach higher tensile properties (modulus, yield stress, strength) without significant loss of ductility.
Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany
Clemens Schafmayer, Jürgen Hartleb, Jürgen Tepel, Stefan Albers, Sandra Freitag, Henry V?lzke, Stephan Buch, Markus Seeger, Birgit Timm, Bernd Kremer, Ulrich R F?lsch, Fred F?ndrich, Michael Krawczak, Stefan Schreiber, Jochen Hampe
BMC Gastroenterology , 2006, DOI: 10.1186/1471-230x-6-36
Abstract: One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry.The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001).The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m2 have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones.Gallstones represent a serious burden for Western healthcare systems: 10–20% of Europeans and Americans carry gallbladder stones [1,2]. The prevalence of gallstone disease is rising, possibly as a result of longer life expectancy and altered nutritional habits. Many gallstones are silent, but symptoms and complications ensue in around 25–50% of cases, necessitating surgical removal of the gallbladder, usually by laparoscopic cholecystectomy [2,3]. Each year, more than 170,000 cholecystectomies are performed in Germany [4]. Cholelithiasis incurs annual medical expenses in excess of $6 billion in the US and is currently the second most expensive digestive disease, exceeded only by reflux disease [5]. The clinical management of
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