Is the repair of oxidative DNA base modifications inducible by a preceding DNA damage induction?

In mammalian cells, 7,8-dihydro-8-oxoguanine (8-oxoG) and some other oxidative guanine modifications are removed from the DNA by base excision repair, which is initiated by OGG1 protein. We have tested whether this repair is inducible in mouse embryonic fibroblasts (MEFs), MCF-7 breast cancer cells and primary human fibroblasts by a pretreatment with the photosensitizer Ro19-8022 plus light, which generates predominantly 8-oxoG, or with methyl methanesulfonate (MMS), which generates alkylated bases and abasic sites (AP sites). The results indicate that the repair rate of the oxidative guanine modifications induced by the photosensitizer was not increased if a priming dose of the oxidative or alkylating agent was applied 6 or 18h prior to a challenging dose, although pretreatments with both agents resulted in two-fold elevated glutathione levels as an indication for an adaptive response. Similarly, the activity of total protein extracts of the cells to incise at a single 8-oxoG residue in an oligonucleotide was unchanged. It has to be concluded that the repair of 8-oxoG is not inducible by oxidative or alkylation damage.     

Is DNA damage the signal for induction of thermal resistance? induction by radiation in yeast

Yeast, as well as higher eukaryotes, are induced to increase thermal resistance (thermotolerance) by prior exposure to a heat stress. Prior exposure to an acute dose of either 60Co gamma or 254-nm ultraviolet radiation, at sublethal or fractionally lethal doses, is shown to cause a marked increase in the resistance of Saccharomyces cerevisiae to killing by heat. Following a radiation exposure, thermal resistance increased with time during incubation in nutrient medium, and the degree of resistance reached was proportional to the dose received. Partial induction by radiation followed by maximum induction by heat did not produce an additive response when compared to a maximum induction by heat alone, suggesting that the same process was induced by both heat and radiation. Irradiation with 254-nm uv light followed by an immediate, partial photoreversal of the pyrimidine dimers with long-wavelength uv light resulted in a reduced level of resistance compared to cells not exposed to the photoreversal light, indicating that the cells specifically recognized pyrimidine dimers as a signal to increase their thermal resistance. Exposure to 254-nm uv or ionizing radiation induced thermal resistance in mutants defective in either excision repair (rad3, uv-sensitive) or recombinational repair (rad52, gamma-sensitive), suggesting that recognition and repair of DNA damage by these systems are not a part of the signal which initiates an increase in resistance to heat. The amount of induction, per unit dose, was greater in the DNA repair-deficient mutants than in the wild-type cells, suggesting that an increase in the length of time during which damage remains in the DNA results in an increase in the effectiveness of the induction. These data indicate that types of DNA damage as diverse as those produced by ionizing radiation and by ultraviolet light are recognized as a signal by the yeast cell to increase its thermal resistance. It is therefore suggested that heat-induced alterations in DNA or in DNA-dependent chromosomal organization may be the signal for heat induction of thermotolerance in this and other eukaryotes.     

Is the Drug-Responsive NADH Oxidase of the Cancer Cell Plasma Membrane a Molecular Target for Adriamycin?

Enhanced growth inhibition and antitumor responses to adriamycin have been observed repeatedly from several laboratories using impermeant forms of adriamycin where entry into the cell was greatly reduced or prevented. Our laboratory has described an NADH oxidase activity at the external surface of plasma membrane vesicles from tumor cells where inhibition by an antitumor sulfonylurea, N-(4-methylphenylsulfonyl)-N-(4-chlorophenyl)urea (LY181984), and by the vanilloid, capsaicin (8-methyl-N-vanillyl-6-noneamide) correlated with inhibition of growth. Here we report that the oxidation of NADH by isolated plasma membrane vesicles was inhibited, as well, by adriamycin. An external site of inhibition was indicated from studies where impermeant adriamycin conjugates were used. The EC₅₀ for inhibition of the oxidase of rat hepatoma plasma membranes by adriamycin was several orders of magnitude less than that for rat liver. Adriamycin cross-linked to diferric transferrin and other impermeant supports also was effective in inhibition of NADH oxidation by isolated plasma membrane vesicles and in inhibition of growth of cultured cells. The findings suggest the NADH oxidase of the plasma membrane as a growth-related adriamycin target at the surface of cancer cells responsive to adriamycin. Whereas DNA intercalation remains clearly one of the principal bases for the cytotoxic action of free adriamycin, this second site, possibly related to a more specific antitumor action, may be helpful in understanding the enhanced efficacy reported previously for immobilized adriamycin forms compared to free adriamycin.     

Is the Notch Locus of DROSOPHILA MELANOGASTER a Tandem Repeat? Correlation of the Genetic Map and Complementation Pattern of Selected Mutations

Correlation of the complementation relationships between the Notch locus alleles fa(g), fa(no), Ax(59d) and nd, with their genetic map order, suggests a tandem repetition within the locus of functionally related sites. This observation is discussed in relation to two hypotheses: (1) that the Notch locus contains a tandem repeat of genetic material; and (2) that the tertiary structure of the Notch locus product has a spiral configuration.     

Is Performance Time a Prerequisite for the Onset and Intensity of the Occlusion-Reperfusion Arrhythmias in Anaesthetised Rats?

The aim of the present study is to investigate the onset and the intensity of arrhythmias in anaesthetized rats as a function of time under a standardized experimental condition, which is composed of 30 min occlusion and 60 min reperfusion. Local bred rats (250-350 g) housed in a 12-h light-dark cycle (lights on at 09.00 h, lights off at 21.00 h) were anaesthetized by sodium thiopentone (60 mg kg^-1 i.p.) and left anterior descending coronary artery ligation method using 6/0 braided silk ligature was used to induce 30 min occlusion and 60-min reperfusion. Animals were randomly allocated into three groups to exposure to 30-min occlusion at 9.00 h and 60 min reperfusion at 9:30 h (Group I, n = 6); to 30 min occlusion at 15.00 h and 60 min reperfusion at 15:30 h (Group II, n = 6); and to 30 min occlusion at 21.00 h and 60 min reperfusion at 21.30 h (Group III, n = 6). ECG and haemodynamic parameters were recorded throughout the experiments. The onset of ventricular ectopic beats (VEBs), number of VEBs, incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) during the periods of occlusion-reperfusion were analysed. Total VF incidence during occlusion were lower than the VT incidence in all groups. Either VT or VF incidences during reperfusion showed same profiles in all groups but VT incidence was 2-fold higher than VF. Time-dependent application of occlusion-reperfusion induced by coronary artery ligation method in the anaesthetized rats did not result in a variation in the onset and the intensity of arrhythmias. The duration of the experimental ischaemia was the principal factor, which determines the time of onset and intensity of the occlusion-reperfusion arrhythmias.     

Is the Performance of a Specialist Herbivore Affected by Female Choices and the Adaptability of the Offspring?

The performance of herbivorous insects is related to the locations of defenses and nutrients found in the different plant organs on which they feed. In this context, the females of herbivorous insect species select certain parts of the plant where their offspring can develop well. In addition, their offspring can adapt to plant defenses. A system where these ecological relationships can be studied occurs in the specialist herbivore, Tuta absoluta, on tomato plants. In our experiments we evaluated: (i) the performance of the herbivore T. absoluta in relation to the tomato plant parts on which their offspring had fed, (ii) the spatial distribution of the insect stages on the plant canopy and (iii) the larval resistance to starvation and their walking speed at different instar stages. We found that the T. absoluta females preferred to lay their eggs in the tomato plant parts where their offspring had greater chances of success. We verified that the T. absoluta females laid their eggs on both sides of the leaves to better exploit resources. We also observed that the older larvae (3^rd and 4^th instars) moved to the most nutritious parts of the plant, thus increasing their performance. The T. absoluta females and offspring (larvae) were capable of identifying plant sites where their chances of better performance were higher. Additionally, their offspring (larvae) spread across the plant to better exploit the available plant nutrients. These behavioral strategies of T. absoluta facilitate improvement in their performance after acquiring better resources, which help reduce their mortality by preventing the stimulation of plant defense compounds and the action of natural enemies.     

When a Text Is Translated Does the Complexity of Its Vocabulary Change? Translations and Target Readerships

In linguistic studies, the academic level of the vocabulary in a text can be described in terms of statistical physics by using a “temperature” concept related to the text''s word-frequency distribution. We propose a “comparative thermo-linguistic” technique to analyze the vocabulary of a text to determine its academic level and its target readership in any given language. We apply this technique to a large number of books by several authors and examine how the vocabulary of a text changes when it is translated from one language to another. Unlike the uniform results produced using the Zipf law, using our “word energy” distribution technique we find variations in the power-law behavior. We also examine some common features that span across languages and identify some intriguing questions concerning how to determine when a text is suitable for its intended readership.     

TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.     

Specificity and Selectivity of a Modified Radioligand Method for Estimating the Binding Activity of β1 Adrenergic Receptors in Human T Lymphocytes

Russian Journal of Bioorganic Chemistry - A radioligand-based method was proposed for quantifying the binding activity of β1-adrenergic receptors (ARs) on the surface of human T lymphocytes....     

The GPIHBP1–LPL Complex Is Responsible for the Margination of Triglyceride-Rich Lipoproteins in Capillaries

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Is DNA barcoding child's play? Science education and the utility of DNA barcoding for the discrimination of UK tree species

We present the findings of a DNA barcoding study of the UK tree flora, implemented as part of an innovative, research‐based science education programme called ‘Tree School’. The UK tree flora comprises native and introduced species, and is a taxonomically diverse study group for the exploration of the potential and limitations of DNA barcoding. The children participating in the project collected voucher specimens and generated DNA barcode sequences from trees and shrubs found in the grounds and surrounding woodlands of a residential field centre in Dorset, UK. We assessed the potential of rbcL and matK markers for amplification and DNA sequencing success and for species discrimination among the 67 tree and shrub species included in this study. Although we achieved 100% PCR amplification and sequencing success for rbcL and matK, mononucleotide repeats affected sequence quality in matK for some taxonomic groups (e.g. Rosaceae). Species discrimination success ranged from 65% to 71% using tree‐based methods to 86% using BLASTN. The occurrence of known hybrids (diploid and polyploid) and their progenitors on the study site reduced the overall species discrimination success for both loci. This study demonstrates that, even in a floristic context, rbcL and matK alone are insufficient for the discrimination of UK tree species, especially where taxonomically complex groups are present. From a science education perspective, DNA barcoding represents a compelling and accessible platform for the engagement of non‐experts in ongoing research, providing an opportunity for them to contribute authentic scientific data to an international research campaign.     

Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling

Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1(-/-) mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β-induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.     

Is there a place for nuclear medicine in the radioembolization of liver tumors?

This is purposely an ultraprovocative title for the broad nuclear medicine community (including radiophysics and radiopharmacy) which leads us to ask questions about how we should correctly use ⁹⁰Yttrium (MSY90) microspheres in the treatment of liver tumors.     

Is Knowing the Age-Order of Alleles in a Sample Useful in Testing for Selective Neutrality?

The most powerful, and most frequently used, test of selective neutrality, based on data consisting of observed allelic frequencies in a sample of genes at some locus, is the procedure of G. A. Watterson. This procedure uses the sample homozygosity F* as the test statistic, and in effect leads to rejection of the hypothesis of selective neutrality if the observed value of F* differs significantly from neutral theory expectations. The homozygosity statistic is invariant under relabeling of the alleles and thus cannot use any further information on the alleles which might be available. We present results which suggest that information concerning the age order of the alleles cannot be used to provide a more powerful testing procedure than that of Watterson.     

Is the PRC for Dark Pulses in LL a Mirror Image of the PRC for Light Pulses in DD in Mice?

The phase-response curves (PRC) for light pulses in continuous darkness (DD) have been described in many mammals, especially in nocturnal rodents. The PRC for dark pulses in continuous light (LL), however, has been described in a few mammals only, in nocturnal for bat and for hamster and in diurnal for Octodon degus, suggesting that this PRC is mirror imaging the PRC for light pulses. Therefore, the effect of 1-h and 3-h lasting dark pulses on the circadian wheel-running activity rhythm of mice in continuous light was investigated and then the PRC for dark pulses in LL was drawn up. For comparison, the effect of 1-h lasting light pulses on the circadian wheel-running activity rhythm of mice in DD was examined and the PRC for light pulses in DD was constructed. It appeared that the PRC for dark pulses, to a certain degree, represents a mirror image of the PRC for light pulses in mice. However, the advance region of this PRC is longer than that of delay. The mechanism of dark pulses action is discussed.     

Is the PRC for Dark Pulses in LL a Mirror Image of the PRC for Light Pulses in DD in Mice?

The phase-response curves (PRC) for light pulses in continuous darkness (DD) have been described in many mammals, especially in nocturnal rodents. The PRC for dark pulses in continuous light (LL), however, has been described in a few mammals only, in nocturnal for bat and for hamster and in diurnal for Octodon degus, suggesting that this PRC is mirror imaging the PRC for light pulses. Therefore, the effect of 1-h and 3-h lasting dark pulses on the circadian wheel-running activity rhythm of mice in continuous light was investigated and then the PRC for dark pulses in LL was drawn up. For comparison, the effect of 1-h lasting light pulses on the circadian wheel-running activity rhythm of mice in DD was examined and the PRC for light pulses in DD was constructed. It appeared that the PRC for dark pulses, to a certain degree, represents a mirror image of the PRC for light pulses in mice. However, the advance region of this PRC is longer than that of delay. The mechanism of dark pulses action is discussed.