Single molecules of double-stranded DNA (dsDNA) were stretched with force-measuring laser tweezers. Under a longitudinal stress of approximately 65 piconewtons (pN), dsDNA molecules in aqueous buffer undergo a highly cooperative transition into a stable form with 5.8 angstroms rise per base pair, that is, 70% longer than B form dsDNA. When the stress was relaxed below 65 pN, the molecules rapidly and reversibly contracted to their normal contour lengths. This transition was affected by changes in the ionic strength of the medium and the water activity or by cross-linking of the two strands of dsDNA. Individual molecules of single-stranded DNA were also stretched giving a persistence length of 7.5 angstroms and a stretch modulus of 800 pN. The overstretched form may play a significant role in the energetics of DNA recombination.
Single chicken erythrocyte chromatin fibers were stretched and released at room temperature with force-measuring laser tweezers. In low ionic strength, the stretch-release curves reveal a process of continuous deformation with little or no internucleosomal attraction. A persistence length of 30 nm and a stretch modulus of Ϸ5 pN is determined for the fibers. At forces of 20 pN and higher, the fibers are modified irreversibly, probably through the mechanical removal of the histone cores from native chromatin. In 40 -150 mM NaCl, a distinctive condensation-decondensation transition appears between 5 and 6 pN, corresponding to an internucleosomal attraction energy of Ϸ2.0 kcal͞mol per nucleosome. Thus, in physiological ionic strength the fibers possess a dynamic structure in which the fiber locally interconverting between ''open'' and ''closed'' states because of thermal fluctuations. The DNA of all eukaryotic cells is organized in the form of chromatin and its structure has been the subject of intense research during the last 25 years. These studies have shown that the basic structural unit of chromatin is the nucleosome comprising the core particle and linker DNA. The core particle contains two of each of four core histones H2A, H2B, H3, and H4, and 146 bp of DNA wrapped around this core. The chromatosome (1, 2) includes the core particle and an additional 20 bp of linker DNA associated to a linker histone (H1 or H5). Although there is still some controversy about the position of the linker histone (3, 4) and the location of H3 and H4 histone tails in the chromatosome, many details have been revealed by the crystal structure of the nucleosome core particle (5-7).Much less is known about the next level of chromatin structure, i.e., the spatial organization of chromatosomes interspersed by linker DNA (8, 9). Many models involving the regular, three-dimensional organization of nucleosomes into chromatin fibers have been proposed (10). Recently, new methods of direct visualization such as scanning force microscopy (11-13) and cryo-electron microscopy (14-16), as well as reinterpretation of older data, indicate that, at low ionic strength at least, nucleosomes in the so-called 30-nm fiber are organized in an irregular three-dimensional zigzag.Chromatin undergoes a process of condensation and decondensation during the cell cycle in vivo. Higher-order structures occur in transcriptionally inactive regions, whereas regions of decondensed nucleosomal arrays often are associated with active chromatin (10). Because in most cell types only a small percentage of the total chromatin content is active at any given time, dynamic changes in the folding state of local chromatin domains must occur to modify the accessibility of the transcription machinery to these domains. These structural transitions may involve H1 removal, histone modifications (acetylation, phosphorylation, or methylation), and changes in the nonhistone protein complement (10,17). Despite the role played by changes in fiber compaction in the regulation of gene ex...
This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.
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