266 research outputs found
CELLmicrocosmos 2.2: advancements and applications in modeling of three-dimensional PDB membranes
Sommer B, Dingersen T, Schneider S, Rubert S, Gamroth C. CELLmicrocosmos 2.2: advancements and applications in modeling of three-dimensional PDB membranes (Conference Abstract). In: Journal of Cheminformatics. Journal of Cheminformatics. Vol 2(Suppl 1):O21. Springer Science and Business Media LLC; 2010
Targeting uracil-DNA glycosylases for therapeutic outcomes using insights from virus evolution
Ung-type uracil-DNA glycosylases are frontline defenders of DNA sequence fidelity in bacteria, plants, and animals; Ungs also directly assist both innate and humoral immunity. Critically important in viral pathogenesis, whether acting for or against viral DNA persistence, Ungs also have therapeutic relevance to cancer, microbial, and parasitic diseases. Ung catalytic specificity is uniquely conserved, yet selective antiviral drugging of the Ung catalytic pocket is tractable. However, more promising precision therapy approaches present themselves via insights from viral strategies, including sequestration or adaptation of Ung for non-canonical roles. A universal Ung inhibition mechanism, converged upon by unrelated viruses, could also inform design of compounds to inhibit specific distinct Ungs. Extrapolating current developments, the character of such novel chemical entities is proposed
Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study
n/aOriginal Publication:Charlotte M Hoog, Olle Brostrom, Tomas Lindahl, Andreas Hillarp, Gerd Larfars and Urban Sjoqvist, Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study, 2010, BMC GASTROENTEROLOGY, (10), 113.http://dx.doi.org/10.1186/1471-230X-10-113Licensee: BioMed Centralhttp://www.biomedcentral.com
Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair
While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination
Male pygmy hippopotamus influence offspring sex ratio
Pre-determining fetal sex is against the random and equal opportunity that both conceptus sexes have by nature. Yet, under a wide variety of circumstances, populations shift their birth sex ratio from the expected unity. Here we show, using fluorescence in situ hybridization, that in a population of pygmy hippopotamus (Choeropsis liberiensis) with 42.5% male offspring, males bias the ratio of X- and Y-chromosome-bearing spermatozoa in their ejaculates, resulting in a 0.4337±0.0094 (mean±s.d.) proportion of Y-chromosome-bearing spermatozoa. Three alternative hypotheses for the shifted population sex ratio were compared: female counteract male, female indifferent, or male and female in agreement. We conclude that there appears little or no antagonistic sexual conflict, unexpected by prevailing theories. Our results indicate that males possess a mechanism to adjust the ratio of X- and Y-chromosome-bearing spermatozoa in the ejaculate, thereby substantially expanding currently known male options in sexual conflict
Cellular Radiosensitivity: How much better do we understand it?
Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies.
Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation
A polymorphism in the CTGF promoter region associated with systemic sclerosis
BackgroundSystemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.MethodsWe genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. We tested the effect of the polymorphism on the transcription of CTGF.ResultsThe GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval [CI], 1.5 to 3.2; P<0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of anti-topoisomerase I antibodies (odds ratio, 3.3; 95% CI, 2.0 to 5.6; P<0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% CI, 1.9 to 5.0; P<0.001). We observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo.ConclusionsThe G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis
Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients.
Tissue engineering, stem cells, cloning, and parthenogenesis: new paradigms for therapy
Patients suffering from diseased and injured organs may be treated with transplanted organs. However, there is a severe shortage of donor organs which is worsening yearly due to the aging population. Scientists in the field of tissue engineering apply the principles of cell transplantation, materials science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Both therapeutic cloning (nucleus from a donor cell is transferred into an enucleated oocyte), and parthenogenesis (oocyte is activated and stimulated to divide), permit extraction of pluripotent embryonic stem cells, and offer a potentially limitless source of cells for tissue engineering applications. The stem cell field is also advancing rapidly, opening new options for therapy. The present article reviews recent progress in tissue engineering and describes applications of these new technologies that may offer novel therapies for patients with end-stage organ failure
Pegylated Interferon and Ribavirin Dosing Strategies to Enhance Sustained Virologic Response
Hepatitis C virus (HCV) affects about 170 million people worldwide and is the most common chronic blood borne infection in the United States. Since the advent of blood screening protocols in the early 1990s, injection drug use has become the leading cause of infection. Hepatitis C can have both hepatic and nonhepatic manifestations of infection. Hepatic manifestations include hepatic fibrosis, cirrhosis, liver cancer, and liver failure. The standard treatment for chronic HCV is combination therapy with pegylated interferon-α and ribavirin. Although pegylated interferon and ribavirin has been used against HCV for close to a decade, advances in therapy have centered on doses and treatment durations. There has been increasing interest in applying on-treatment response or viral kinetics to predict antiviral response rates and shape therapeutic intervention. Protease inhibitors are a promising adjuvant to combination therapy, but their efficacy and safety are still under investigation
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