Folding and unfolding of a triple-branch DNA molecule with four conformational states

Single-molecule experiments provide new insights into biological processes hitherto not accessible by measurements performed on bulk systems. We report on a study of the kinetics of a triple-branch DNA molecule with four conformational states by pulling experiments with optical tweezers and theoretical modelling. Three distinct force rips associated with different transitions between the conformational states are observed in the folding and unfolding trajectories. By applying transition rate theory to a free energy model of the molecule, probability distributions for the first rupture forces of the different transitions are calculated. Good agreement of the theoretical predictions with the experimental findings is achieved. Furthermore, due to our specific design of the molecule, we found a useful method to identify permanently frayed molecules by estimating the number of opened basepairs from the measured force jump values.Comment: 17 pages, 12 figure

The parameters of Menzerath-Altmann law in genomes

The relationship between the size of the whole and the size of the parts in language and music is known to follow Menzerath-Altmann law at many levels of description (morphemes, words, sentences...). Qualitatively, the law states that larger the whole, the smaller its parts, e.g., the longer a word (in syllables) the shorter its syllables (in letters or phonemes). This patterning has also been found in genomes: the longer a genome (in chromosomes), the shorter its chromosomes (in base pairs). However, it has been argued recently that mean chromosome length is trivially a pure power function of chromosome number with an exponent of -1. The functional dependency between mean chromosome size and chromosome number in groups of organisms from three different kingdoms is studied. The fit of a pure power function yields exponents between -1.6 and 0.1. It is shown that an exponent of -1 is unlikely for fungi, gymnosperm plants, insects, reptiles, ray-finned fishes and amphibians. Even when the exponent is very close to -1, adding an exponential component is able to yield a better fit with regard to a pure power-law in plants, mammals, ray-finned fishes and amphibians. The parameters of Menzerath-Altmann law in genomes deviate significantly from a power law with a -1 exponent with the exception of birds and cartilaginous fishes.Comment: Typos and little inaccuracies corrected. Title and references updated (the previous update failed

Aplastic Anemia and Severe Myelosuppression with Boceprevir or Simeprevir-Containing Hepatitis C Virus Treatment

The addition of the new protease inhibitors (PIs) to peg-interferon (IFN) and ribavirin (RBV), approved for chronic hepatitis C, has clearly improved sustained virological response (SVR) rates although several adverse events have been reported with this regimens, including mild hematological toxicity. Moreover, severe pancytopenia and aplastic anemia during triple therapy with telaprevir has recently been described in seven patients. We report here two cases of severe agranulocytosis/aplastic anemia using boceprevir or simeprevir in interferon-based combination and 2 additional cases of severe myelosupression in IFN-free therapy with sofosbuvir and simeprevir plus RBV. Our observations suggest that PIs could have a sort of class-effect in developing severe hematologic toxicity or, at least, an additive interaction with other potentially myelotoxic agents such as IFN or RBV that are used in the classical regimens against HCV. Unfortunately, the mechanisms behind this phenomenon are currently unknown. In conclusion, given the lifethreatening character of these complications, close monitoring is mandatory in patients under PIs based therapy to promptly detect serious hematological toxicities and to carefully evaluate treatment discontinuation. Prospective studies assessing the usefulness of RBV in the era of new IFN-free combinations are needed

Correction: Neutrophil and Monocyte Function in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy with Regimens Containing Protease Inhibitors with and without Interferon.

[This corrects the article DOI: 10.1371/journal.pone.0166631.]

Neutrophil and Monocyte Function in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy with Regimens Containing Protease Inhibitors with and without Interferon

Real-life data showed an increased incidence of bacterial infections in patients with advanced liver disease receiving a protease inhibitor (PI)-containing antiviral regimen against hepatitis C (HCV). However, the causes of this event are unknown. We hypothesized that PIs might impair innate immune responses through the inhibition of proteases participating in the anti-bacterial functions of neutrophils and monocytes. The aims of the study were to assess phagocytic and oxidative burst capacity in neutrophils and monocytes obtained from patients receiving a PI containing-antiviral regimen, and to determine cytokine secretion after neutrophil stimulation with flagellin. Forty patients with chronic HCV (80% with cirrhosis) were enrolled in the study, 28 received triple therapy (Group A) with pegylated-interferon and ribavirin for 4 weeks followed by the addition of a PI (telaprevir, boceprevir or simeprevir), and 12 patients received an interferon-free regimen (Group B) with simeprevir and sofosbuvir. Phagocytosis and oxidative burst capacity were analyzed by flow cytometry at baseline, week 4, and week 8 of therapy. In neutrophils from Group A patients, oxidative burst rate and oxidative enzymatic activity per cell significantly decreased throughout the study period (p = 0.014 and p = 0.010, respectively). Pairwise comparisons showed a decrease between baseline and week 4 and 8 of therapy. No differences were observed after the introduction of the PI. The oxidative enzymatic activity per cell in monocytes significantly decrease during the study period (p = 0.042) due to a decrease from baseline to week 8 of therapy (p = 0.037) in patients from Group A. None of these findings were observed in Group B patients. Cytokine secretion did not significantly change during the study in both groups. In conclusion, our data suggest that the use interferon (rather than the PI) has a deleterious effect on neutrophil and monocyte phagocytic and oxidative burst capacity in this cohort of patients with HCV-related advanced liver fibrosis

Oxidative burst capacity of neutrophils.

<p>Panel A and B show the burst rate (B-R) in patients treated with triple therapy and IFN-free regimen, respectively. Panel C and D show the enzymatic activity per cell (median fluorescence intensity, B-MFI) in patients treated with triple therapy and IFN-free regimen, respectively. Data are analyzed at baseline (before starting antiviral therapy), and at week 4 and 8 of therapy. * These comparisons were performed by Friedman tests.</p