Asthma is a heterogeneous inflammatory disease characterized by increased airway hyper-responsiveness to external stimuli such as irritants. One may speculate that asthmatics are more sensitive to irritants in the air than healthy subjects, i.e. react at lower concentrations. We reviewed the scientific support for this speculation and investigated to what extent asthma is considered when setting exposure limits and guidance values. We found that the experimental studies comparing healthy and asthmatic subjects are often inconclusive. Still, the available studies are underused, by expert committees and industry alike. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a benchmark concentration analysis suggests a nine-fold difference in sensitivity. Based on these data a default assessment factor of 10 is suggested when setting exposure limits and guidance values for irritants. INTRODUCTION Smoking is an independent cause of cervical cancer, which is the 4th most common malignancy in women. It is currently not known if tobacco consumption causes chromosomal damage (which is a hallmark of human cancer) in cervical cells and if age and the hormonal status have an impact on tobacco induced genetic instability in the cervix. METHODS We conducted a study with pre- and post-menopausal women smokers and never-smokers (25/group). Smokers consumed 30 light/medium cigarettes/day and were matched with the non-smoking group. Cervical cells were analyzed for induction of micronuclei (MN) which are caused by structural/numerical chromosomal aberrations; additionally, other nuclear anomalies reflecting genomic instability and cytotoxicity were scored. Furthermore, the frequencies of basal cells were recorded which reflect the mitotic activity of the mucosa. RESULTS MN and other abnormalities were increased in both groups of smokers. The effects were most pronounced in postmenopausal smokers (i.e. 2-fold higher) compared to premenopausal smokers. Also the number of basal cells (indicative for cell proliferation) was clearly enhanced in older women. Tar and nicotine had no detectable impact on chromosomal damage but a clear association with pack-years was observed. CONCLUSIONS Smoking increased chromosomal instability, cytotoxicity and induced cell divisions in cervical mucosa cells of pre- and post-menopausal women. The effects were more pronounced in the latter group indicating a higher risk for diseases (including cancer) that are causally related to DNA damage. Trivalent chromium has been proposed to be transported in vivo from the bloodstream to the tissues via endocytosis by transferrin (Tf), the major iron transport protein in the blood. While both Cr(III) binding and release from Tf have been proposed to be too slow to be physiologically relevant, recent kinetic studies under physiological conditions demonstrate that Cr(III) binding and release are sufficiently fast to occur during the time of the endocytosis cycle (circa 15 min). Consequently, the release of Cr(III) from human and bovine serum Tf has been examined under conditions mimicking an endosome during endocytosis. These studies have also found that Cr(III)2-Tf can exist in multiple conformations giving rise to different spectroscopic properties and different rates of Cr(III) release. Time-dependent spectroscopic studies of the binding and release of Cr(III) from human serum Tf have been used to identify three different conformations of Cr(III)2-Tf. The conformation of Cr(III)2-Tf used in most previous studies forms too slowly to be physiologically relevant and slowly releases Cr(III) in endosomal pH range. The conformation formed between 5 min to 60 min after the addition of Cr(III) to apoTf at pH 7.4 in 25 mM bicarbonate resembles the conformation of Cr(III)2-Tf in its complex with Tf receptor (TfR) and loses Cr(III) rapidly at endosomal pH, although not as fast as the Tf-TfR complex. The significance of these conformations and the potential role of Tf in detoxification of Cr(III) are described. Peptide tags are extensively used for affinity purification of proteins. In an optimal case, these tags can be completely removed from the purified protein by a specific protease mediated hydrolysis. However, the interactions of these tags with the target protein may also be utilized for the modulation of the protein function. Here we show that the C-terminal hexahistidine (6 × His) tag can influence the catalytic activity of the nuclease domain of the Colicin E7 metallonuclease (NColE7) used by E. coli to kill competing bacteria under stress conditions. This enzyme non-specifically cleaves the DNA that results in cytotoxicity. We have successfully cloned the genes of NColE7 protein and its R447G mutant into a modified pET-21a DNA vector fusing the affinity tag to the protein upon expression, which would be otherwise not possible in the absence of the gene of the Im7 inhibitory protein. This reflects the inhibitory effect of the 6 × His fusion tag on the nuclease activity, which proved to be a complex process via both coordinative and non-specific steric interactions. The modulatory effect of Zn2+ ion was observed in the catalytic activity experiments. The DNA cleavage ability of the 6 × His tagged enzyme was first enhanced by an increase of metal ion concentration, while high excess of Zn2+ ions caused a lower rate of the DNA cleavage. Modelling of the coordinative effect of the fusion tag by external chelators suggested ternary complex formation instead of removal of the metal ion from the active center. Colorectal cancer is the third most common type of cancer and has a high incidence in developed countries. At present, specific treatments are being required to allow individualized therapy depending on the molecular alteration on which the drug may act. The aim of this project is to evaluate whether HPTSC and HPTSC* thiosemicarbazones (HPTSC = pyridine-2-carbaldehyde thiosemicarbazone and HPTSC* = pyridine-2-carbaldehyde 4N-methylthiosemicarbazone), and their complexes with different transition metal ions as Cu(II), Fe(III) and Co(III), have antitumor activity in colon cancer cells (HT-29 and SW-480), that have different oncogenic characteristics. Cytotoxicity was evaluated and the involvement of oxidative stress in its mechanism of action was analyzed by quantifying the superoxide dismutase activity, redox state by quantification of the thioredoxin levels and reduced/oxidized glutathione rate and biomolecules damage. The apoptotic effect was evaluated by measurements of the levels of caspase 9 and 3 and the index of histones. All the metal-thiosemicarbazones have antitumor activity mediated by oxidative stress. The HPTSC*-Cu was the compound that showed the best antitumor and apoptotic characteristics for the cell line SW480, that is KRAS gene mutated. Vorinostat (suberoylanilide hydroxamic acid; SAHA) and Belinostat are two hydroxamate-based histone deacetylase inhibitors that are used clinically as potent anti-cancer agents. Their metabolic breakdown into inactive metabolites such as carboxylic acid and glucuronic derivatives results in them having short half-lives, which can negatively impact their pharmacokinetic profiles. Herein we report the potential of both Vorinostat and Belinostat to also act as nitric oxide donors under both chemical and biological ex vivo experimental conditions. More specifically, using ruthenium(III) as an effective NO scavenger, we were able to establish, in the first instance, that both Vorinostat and Belinostat had the capacity to release NO under chemical conditions. Both Vorinostat and Belinostat were then shown to cause vascular relaxation of rat aorta via NO-mediated activation of the haem-containing guanylate cyclase enzyme. A summary of our findings is reported herein. BACKGROUND Young adulthood has the highest rates of alcohol use and high-risk drinking behavior. This period is also a critical neurodevelopmental stage, with neural insults having a profound neurotoxic effect on the brain. Cortical gyrification is thought, in part, to reflect early brain maturation (e.g., hypogyrification in fetal alcohol syndrome). There is also evidence that cortical gyrification is sensitive to later-life events (e.g., fluctuations in malnutrition in young adults). However, no study has examined how alcohol use in young adulthood is associated with cortical gyrification. METHODS We examined the associations between cortical gyrification with lifetime alcohol use and past year hangover symptoms in young adults (N = 78). RESULTS Lifetime alcohol use was associated with hypogyria in multiple cortical regions (rs ≤ -.27, ps ≤ .0159; right orbitofrontal, right temporal pole, and left lateral occipital). Further, past year hangover symptoms were associated with hypogyria (rs ≤ -.27, ps ≤ .0034), overlapping with lifetime alcohol use (right orbitofrontal and left lateral occipital). Hangover symptoms were also uniquely associated with hypogyria of other cortical regions (rs ≤ -.30, ps ≤ .0002; right parahippocampal gyrus, left inferior temporal/parahippocampal gyrus and right anterior insula). CONCLUSIONS Thus, results suggest that young adulthood is a critical period for targeted prevention and intervention, especially for individuals exhibiting heavy alcohol consumption and high-risk drinking behavior. Hazardous drinking is prevalent among college students, yet few seek treatment. Anxiety sensitivity AS is one factor with relevance to drinking. Yet, there are no known estimates of the prevalence of elevated AS among hazardous drinkers. The current study sought to estimate the prevalence of elevated AS among hazardous drinking college students and to examine relations between AS and hazardous drinking. Data from 1257 students Mage = 22.08; 80.4 % female; 76.8 % racial/ethnic minorities was employed. Approximately one third (30.7 %) of the sample met criteria for hazardous drinking. Among hazardous drinkers, 77.5 % had clinically elevated AS; similar rates were evidenced across sex and race/ethnicity. Hazardous drinkers reported significantly greater AS scores than moderate drinkers and non-drinkers (p  less then  0.001; η2 = 0.09). Those with elevated AS were more than three times more likely to be hazardous drinkers (p  less then  0.001). Among hazardous drinkers, those with elevated AS had more severe drinking levels (p  less then  0.001; Cohen’s d=0.07) as well as greater likelihood, number, and disturbance related to use of other substances (p’s from less then 0.001-0.005; Cohen’s d’s from 0.01 to 0.02). Findings from this study suggest that most hazardous drinkers have elevated AS, and that elevated AS is associated with a substantially higher likelihood of being a hazardous drinker. Hazardous drinkers with elevated AS report more severe drinking and other substance use than those with normative AS. There may be practical clinical benefit of implementing focus on AS to reduce hazardous drinking in college settings. V.INTRODUCTION Despite the demonstrated benefit of methadone, the incidence opioid-related overdose, and its associated mortality continues to rise at an alarming rate. The impact of high prevalence comorbid features such as chronic liver disease (CLD) on methadone treatment response remain unclear. AIM To determine whether CLD is associated with poor response to methadone treatment. METHODS Using a well-established multi-center cohort from the Genetics of Opioid Addiction Study (GENOA), we evaluated if presence of CLD among 1234 eligible patients with opioid use disorder receiving methadone treatment impacted health and behavioural responses to treatment. CLD was classified as any liver disorder/dysfunction present for a minimum period of six months. Serial urine toxicology assessments were used to determine treatment response. The effect of CLD was determined using a multi-variable logistic regression model. RESULTS CLD was present in 25 % (n = 314) of the population. On average, patients with CLD were found to be older (mean age 44 vs 36 years, p less then 0.