Structural Insights into DNA Polymerase β Deterrents for Misincorporation Support an Induced-Fit Mechanism for Fidelity

AbstractDNA polymerases generally select the correct nucleotide from a pool of structurally similar molecules to preserve Watson-Crick base-pairing rules. We report the structure of DNA polymerase β with DNA mismatches situated in the polymerase active site. This was achieved by using nicked product DNA that traps the mispair (template-primer, A-C or T-C) in the nascent base pair binding pocket. The structure of each mispair complex indicates that the bases do not form hydrogen bonds with one another, but form a staggered arrangement where the bases of the mispair partially overlap. This prevents closure/opening of the N subdomain that is believed to be required for catalytic cycling. The partially open conformation of the N subdomain results in distinct hydrogen bonding networks that are unique for each mispair. These structures define diverse molecular aspects of misinsertion that are consistent with the induced-fit model for substrate specificity

Concentrations of Polychlorinated Biphenyls (PCB’s), Chlorinated Pesticides, and Heavy Metals and Other Elements in Tissues of Belugas, Delphinapterus leucas, from Cook Inlet

Tissues from Cook Inlet beluga whales, Delphinapterus leucas, that were collected as part of the Alaska Marine Mammal Tissue Archival Project were analyzed for polychlorinated biphenyls (PCB’s), chlorinated pesticides, and heavy metals and other elements. Concentrations of total PCB’s (ΣPCB’s), total DDT (ΣDDT), chlordane compounds, hexachlorobenzene (HCB), dieldrin, mirex, toxaphene, and hexachlorocyclohexane (HCH) measured in Cook Inlet beluga blubber were compared with those reported for belugas from two Arctic Alaska locations (Point Hope and Point Lay), Greenland, Arctic Canada, and the highly contaminated stock from the St. Lawrence estuary in eastern Canada. The Arctic and Cook Inlet belugas had much lower concentrations (ΣPCB’s and ΣDDT were an order of magnitude lower) than those found in animals from the St. Lawrence estuary. The Cook Inlet belugas had the lowest concentrations of all (ΣPCB’s aver-aged 1.49 ± 0.70 and 0.79 ± 0.56 mg/kg wet mass, and ΣDDT averaged 1.35 ± 0.73 and 0.59 ± 0.45 mg/kg in males and females, respectively). Concentrations in the blubber of the Cook Inlet males were significantly lower than those found in the males of the Arctic Alaska belugas (ΣPCB’s and ΣDDT were about half). The lower levels in the Cook Inlet animals might be due to differences in contaminant sources, food web differences, or different age distributions among the animals sampled. Cook Inlet males had higher mean and median concentrations than did females, a result attributable to the transfer of these compounds from mother to calf during pregnancy and during lactation. Liver concentrations of cadmium and mercury were lower in the Cook Inlet belugas (most cadmium values were <1 mg/kg and mercury values were 0.704–11.42 mg/kg wet mass), but copper levels were significantly higher in the Cook Inlet animals (3.97–123.8 mg/kg wet mass) than in Arctic Alaska animals and similar to those reported for belugas from Hudson Bay. Although total mercury levels were the lowest in the Cook Inlet population, methylmercury concentrations were similar among all three groups of the Alaska animals examined (0.34–2.11 mg/kg wet mass). As has been reported for the Point Hope and Point Lay belugas, hepatic concentrations of silver were r

Feasibility of self-structured current accessed bubble devices in spacecraft recording systems

The self-structured, current aperture approach to magnetic bubble memory is described. Key results include: (1) demonstration that self-structured bubbles (a lattice of strongly interacting bubbles) will slip by one another in a storage loop at spacings of 2.5 bubble diameters, (2) the ability of self-structured bubbles to move past international fabrication defects (missing apertures) in the propagation conductors (defeat tolerance), and (3) moving bubbles at mobility limited speeds. Milled barriers in the epitaxial garnet are discussed for containment of the bubble lattice. Experimental work on input/output tracks, storage loops, gates, generators, and magneto-resistive detectors for a prototype device are discussed. Potential final device architectures are described with modeling of power consumption, data rates, and access times. Appendices compare the self-structured bubble memory from the device and system perspectives with other non-volatile memory technologies

Effects of fluoxetine on the oral environment of bulimics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73809/1/j.1399-302X.1993.tb00545.x.pd

Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation

Aims: To understand the changing trends in Atrial Fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role. Methods and Results: We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality and mortality to incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100,000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women versus men in 1990 to 74.5% higher in women in 2017). Conclusion: AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from A

The effects of continuous naltrexone infusions on diet preferences are modulated by adaptation to the diets

Two groups of male rats were placed on a feeding regimen in which a fat/protein diet and a carbohydrate/protein diet were available ad lib. Naltrexone was infused via osmotic minipumps either at the time the diets were introduced or after one week of adaptation to the diets. In rats adapted to the diets, naltrexone caused a decrease in the intakes of fat/protein and carbohydrate/protein diets. Relative preferences for the two diets were generally unchanged. In contrast, when naltrexone was infused at the time of introduction of the diets, a polarization phenomenon was observed: rats tended to consume nearly all of their daily calories from either one diet or the other. Six rats (out of 10) showed a stronger preference for the carbohydrate/protein diet than did any of the saline-treated rats, while 3 showed a stronger preference for the fat/protein diet than did any of the saline-treated rats. Thus, the effect was not diet- or macronutrient-specific. These preferences became significantly less extreme after termination of naltrexone infusions. Conditioned aversions and naltrexone-induced reductions in exploratory behavior are discussed as potential explanations for this polarization effect. These results indicate that naltrexone has differential effects on the development versus the maintenance of diet preferences. Further, they emphasize the importance of examining individual differences as well as baseline preferences in studies on the control of intake and diet selection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30229/1/0000622.pd

The relationship between saccharin and alcohol intake in rats

Male rats were given daily sessions during which a palatable saccharin solution was available. Based on intakes averaged over 3 days, groups with low, intermediate, or high intake of saccharin were formed. These rats were then given daily sessions in which alcohol (2-8%) or water were available. Initially, sessions were conducted with rats on a food restriction schedule; in later sessions, food was available ad lib. When rats were food restricted, there were no differences among the groups in terms of alcohol or water intake. When the food restriction schedule was discontinued, alcohol intake in the intermediate and high saccharin intake groups was generally higher than that of the low saccharin group. On the final series of alcohol sessions, the high saccharin group consumed significantly more 2% and 6% alcohol than the low saccharin group. These results are consistent with reports which have found that rats selected for high or low alcohol intake have corresponding high and low intakes of saccharin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30072/1/0000442.pd

Fat-preferring rats consume more alcohol than carbohydrate-preferring rats

Rats with a genetic preference for alcohol (ETOH) have been found to consume more dietary fat then ETOH nonpreferring rats. We therefore hypothesized that rats selected on the basis of fat and carbohydrate (CHO) preferences would differ in ETOH intake. Patterns of macronutrient self-selection were determined by allowing rats to select diets from separate source of CHO, fat and protein. Subsequently, CHO- and fat-preferring groups were formed. All rats were then returned to a lab chow diet and trained to drink ETOH (4-14%) during one hour of access per day. Food restriction was used only in the first three weeks of the procedure. On the final drinking session, water and ETOH were alternated on a daily basis. Fat-preferring rats consumed significantly more ETOH than water, CHO-preferring rats consumed approximately equal amounts of ETOH and water. Futhermore, fat-preferring rats consumed more ETOH than CHO-preferring rats. This study suggests that there may be a common mechanism underlying diet preference and oral intake of ETOH.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29255/1/0000312.pd