Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco-Specific Nitrosamines

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) are tobacco-specific nitrosamines present in tobacco products and smoke. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers. These Group 1 human carcinogens are metabolized to reactive intermediates that alkylate DNA. This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds. This DNA route generates 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxycytosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxythymidine, and O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine as well as unstable adducts which dealkylate to release 4-hydroxy-1-{3-pyridyl)-1-butanone or depyriminidate/depurinate to generate abasic sites. There are multiple repair pathways responsible for protecting against the genotoxic effects of these adducts, including adduct reversal as well as base and nucleotide excision repair pathways. Data indicate that several DNA adducts contribute to the overall mutagenic properties of pyridyloxobutylating agents. Which adducts contribute to the carcinogenic properties of this pathway are likely to depend on the biochemistry of the target tissue

Distribution of the birds of the Philippines: biogeography and conservation priorities

The Philippine islands hold a concentration of species diversity and endemism of global importance, yet few studies have analyzed biogeographic patterns or attempted to prioritize areas for conservation within the archipelago. We analyzed distributions of 386 species on 28 Philippine islands and island groups, documenting intense concentration of species richness, especially of endemic species, on the two largest islands, Mindanao and Luzon. Factors identified as influencing species richness included island area, maximum elevation, and Pleistocene patterns of connection and isolation. Reserve systems were developed based on heuristic complementarity algorithms, and compared with the existing Integrated Protected Areas (IPAS) system in the country, showing that IPAS is an impressive first step towards protecting avian diversity in the country. Addition of presently proposed reserves on Palawan and Mindoro would make IPAS a near-optimal reserve design, at least at the level of island representation. Important challenges remain, however, with regard to design of reserve systems within islands to represent complete island avifaunas

Assessing the Risk of 100-year Freshwater Floods in the Lamprey River Watershed of New Hampshire Resulting from Changes in Climate and Land Use

What is the coastal resource issue the project sought to address? Both the magnitude and frequency of freshwater flooding is on the rise in seacoast NH and around much of New England. In the Great Bay watershed, this is the result of two primary causes: 1) increases in impervious surface stemming from a three-to-four fold increase in developed land since 1962; and 2) changing rainfall patterns in part exemplified by a doubling in the frequency of extreme weather events that drop more than 4 inches of precipitation in less than 48 hours (Wake et al., 2011) over the same time period. Moreover, the size of the 100-year precipitation event in this region has increased 26% from 6.3 inches to 8.5 inches from the mid 1950’s to 2010 (NRCC and NRCS, 2012). One consequence is the occurrence of three 100-year floods measured on the Lamprey River at Packers Falls since 1987, and a fourth if the three days of flooding in March of 2010 had occurred instead in two days (Figure 1). Flooding events are expected to continue to increase in magnitude and frequency as land in the watershed is further developed and climate continues to change in response to anthropogenic forcing (e.g., Hayhoe et el., 2007; IPCC, 2007; Karl et al., 2009). Land use management strategies, in particular low impact development (LID) zoning requirements, are one strategy that communities can employ for increased resiliency to flooding with the greatest influence in urban environments

Enhanced Survival and Neuronal Differentiation of Adrenal Chromaffin Cells Cografted into the Striatum with NGF-producing Fibroblasts

Although adrenal medullary chromaffin cells have been used extensively for intracerebral grafting, their survival has generally been poor. Improved survival of the implanted cells has been achieved by exposing the chromaffin cells to NGF in vivo. Culture studies have shown, however, that chromaffin cells are converted into sympathetic neurons when NGF is included in the medium. The degree to which such a transdifferentiation may occur in vivo has not been determined. We assessed the effects of cografting chromaffin cells with primary fibroblasts genetically engineered to express NGF. Chromaffin cells from 10 d old rats were implanted with NGF-producing or beta- galactosidase-producing primary fibroblasts (control fibroblasts) into the striatum of 6-hydroxydopamine treated adult rats of the same strain. Eight weeks postgrafting, chromaffin cells cografted with NGF- producing fibroblasts displayed many of the features of mature sympathetic neurons such as large somata, long processes, transmitter vesicles similar to those found in neurons, and positive immunolabeling for the neuronal markers neurofilament, MAP2 and SCG10. Chromaffin- derived neuron number was also significantly enhanced in the presence of NGF-producing fibroblasts. While control fibroblasts were also found to increase chromaffin cell number above that of chromaffin cells grafted alone, the control fibroblasts did not induce neuronal transdifferentiation. These results demonstrate that chromaffin cells cografted with NGF-producing fibroblasts undergo transdifferentiation in vivo and express many characteristics of mature sympathetic neurons. The consequences of this transdifferentiation on the long term survival and function of the transplanted cells in vivo remain to be clarified

Conclusions about Niche Expansion in Introduced Impatiens walleriana Populations Depend on Method of Analysis

Determining the degree to which climate niches are conserved across plant species' native and introduced ranges is valuable to developing successful strategies to limit the introduction and spread of invasive plants, and also has important ecological and evolutionary implications. Here, we test whether climate niches differ between native and introduced populations of Impatiens walleriana, globally one of the most popular horticultural species. We use approaches based on both raw climate data associated with occurrence points and ecological niche models (ENMs) developed with Maxent. We include comparisons of climate niche breadth in both geographic and environmental spaces, taking into account differences in available habitats between the distributional areas. We find significant differences in climate envelopes between native and introduced populations when comparing raw climate variables, with introduced populations appearing to expand into wetter and cooler climates. However, analyses controlling for differences in available habitat in each region do not indicate expansion of climate niches. We therefore cannot reject the hypothesis that observed differences in climate envelopes reflect only the limited environments available within the species' native range in East Africa. Our results suggest that models built from only native range occurrence data will not provide an accurate prediction of the potential for invasiveness if applied to areas containing a greater range of environmental combinations, and that tests of niche expansion may overestimate shifts in climate niches if they do not control carefully for environmental differences between distributional areas

Stability of methylation markers in head and neck squamous cell carcinoma

BackgroundAs cancer progresses, methylation patterns change to promote the tumorigenic phenotype. However, stability of methylation markers over time and the extent that biopsy samples are representative of larger tumor specimens are unknown. This information is critical for clinical use of such biomarkers.MethodsNinety‐eight patients with tumor specimens from 2 timepoints were measured for DNA methylation in the promoter regions across 4 genes.ResultsThere were no significant differences in overall methylation of CCNA1 (cyclin A1), NDN (necdin), deleted in colorectal carcinoma (DCC), and cluster of differentiation 1a (CD1A) within paired specimens (p values = .56, .17, .66, and .58, respectively). All genes showed strong correlations between paired specimens across time. Methylation was most consistent for CCNA1 and NDN over time.ConclusionThis report provides the first evidence that methylation markers measured in biopsy samples are representative of gene methylation in later specimens and suggests that biopsy markers could be representative biomarkers for use in defining personalized treatment utilizing epigenetic changes. © 2015 Wiley Periodicals, Head Neck 38: E1325–E1331, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/1/hed24223.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/2/hed24223_am.pd

Antiplatelet Therapy Changes for Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From the TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) Study

BACKGROUND: Guidelines recommend P2Y12 inhibitor therapy for 1 year after myocardial infarction (MI), yet little guidance is provided on antiplatelet management for patients with recurrent ischemic events during that year. We describe changes in P2Y12 inhibitor type among patients with recurrent ischemic events in the first year after MI. METHODS AND RESULTS: The TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study enrolled 12 365 patients with MI treated with percutaneous coronary intervention. We examined whether P2Y12 inhibitor choice changed among patients with recurrent MI, stent thrombosis, and/or unplanned revascularization during the first year after MI, and modeled factors associated with P2Y12 inhibitor intensification (changing clopidogrel to prasugrel or ticagrelor). In the first year after MI, 1414 patients (11%) had a total of 1740 recurrent ischemic events (771 recurrent MIs, 969 unplanned revascularizations, and 165 stent thromboses). Median time to the first recurrent ischemic event was 154 days (25th-75th percentiles, 55-287 days). Of those with recurrent ischemic events, 101 of 1092 (9.3%) occurring in clopidogrel-treated patients led to P2Y12 inhibitor intensification. Recurrent events involving stent thrombosis or MI were the strongest factors associated with P2Y12 inhibitor intensification, yet only 40% of patients with stent thrombosis and 14% of patients with recurrent MI had P2Y12 inhibitor intensification. Increasing age and longer time from the index MI were associated with lower likelihood for intensification. CONCLUSIONS: Few patients after MI with a recurrent ischemic event who were taking clopidogrel switched to a more potent P2Y12 inhibitor, even after stent thrombosis events. Specific guidance is needed for patients who have recurrent ischemic events, particularly when closely spaced. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503

Stress among UK academics : identifying who copes best?

This paper examined the levels of stress and coping strategies among UK academics. Adopting a positive psychology approach, the influence of the character strengths of hope, optimism, gratitude and self-efficacy, on stress, subjective well-being (SWB), and mental health (GHQ) was examined in 216 academics in a UK university. The study explored the relationship between coping styles and work-coping variables of sense of coherence and work locus of control and stress. No significant differences on the stress, well-being and mental health measures were found for participants' gender, whether in full-time or part-time employment and level of seniority within the university. Participants using problem-focussed coping experienced lower levels of stress while dysfunctional coping was a positive predictor of stress. Hope agency, hope pathway, gratitude, optimism and self-efficacy were the strongest positive predictors of satisfaction with life (SWL), while levels of perceived stress negatively predicted SWL. Gratitude, hope agency and self-efficacy positively predicted positive affect, while stress was a negative predictor. Gratitude, hope agency, self-efficacy and optimism were negative significant predictors of negative affect while stress was a positive predictor. Gratitude positively predicted mental health, while stress was a negative predictor and optimism was a significant moderator of the relationship between stress and mental health. Academics with higher levels of gratitude, self-efficacy, hope and optimism report lower levels of stress at work and higher levels of well-being as measured by higher life satisfaction, higher positive affect and lower negative affect. New approaches to stress management training are suggested based on these findings