Energetics of Protein-DNA Interactions

Protein-DNA interactions are vital for many processes in living cells, especially transcriptional regulation and DNA modification. To further our understanding of these important processes on the microscopic level, it is necessary that theoretical models describe the macromolecular interaction energetics accurately. While several methods have been proposed, there has not been a careful comparison of how well the different methods are able to predict biologically important quantities such as the correct DNA binding sequence, total binding free energy, and free energy changes caused by DNA mutation. In addition to carrying out the comparison, we present two important theoretical models developed initially in protein folding that have not yet been tried on protein-DNA interactions. In the process, we find that the results of these knowledge-based potentials show a strong dependence on the interaction distance and the derivation method. Finally, we present a knowledge-based potential that gives comparable or superior results to the best of the other methods, including the molecular mechanics force field AMBER99

Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial.

ObjectiveTo better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions.BackgroundAdhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo.MethodsWe undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia.ResultsOf the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.ConclusionIn this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints

CELLULAR EVENTS IN THE IMMUNE RESPONSE : ANALYSIS AND IN VITRO RESPONSE OF MOUSE SPLEEN CELL POPULATIONS SEPARATED BY DIFFERENTIAL FLOTATION IN ALBUMIN GRADIENTS

Cell suspensions from the spleens of normal mice or mice injected with sheep erythrocytes were separated on a discontinous bovine serum albumin density gradient. Four bands or subpopulations were obtained and were assayed for antibody-forming cells, and for antigen-sensitive precursor cells. The antibody-forming cells were assayed by the hemolytic plaque assay and the antigen-sensitive precursors were assayed by the number of plaque-forming cells which developed after 3 or 5 day's culture with antigen. It was found that both antibody-forming cells and their precursors were present in the denser region of the gradient when spleen cell suspensions were taken from unimmunized mice. In contrast, both antibody-forming cells and precursors floated to the top in cell suspensions from mice sacrificed 1, 2, or 3 days after antigen injection. The change in density was detectable as early as 12 hr and was complete by 18 hr. The cell which changed in density was specific for the antigen that brought about that change. The significance of these findings is discussed

Hydrology and Water Quality of the Copper-Nickel Study Region, Northeastern Minnesota

Saint Paul: USGS.This 35-year old hydrologic study documents conditions in the Cu-NU region of Minnesota’s Iron Range. It is primarily a technical report, but its main value is the baseline data provided, and that it contains a water budget for the area. It’s primary message for decision-makers is that “the introduction of trace metals from future mining to the ground-water system can be reduced if tailings basins and stockpiles are located on material of low permeability, such as till, peat, or bedrock." Key segments are extracted and reproduced below. Abstract: "Data were collected on the hydrology of the Copper-Nickel study region, to identify the location and nature of ground-water resources, determine the flow characteristics and general quality of the major streams, and determine the potential effects of mining copper and nickel on the hydrologic system. Ground-water investigations indicate that water generally occurs in local flow systems within surficial deposits and in fractures in the upper few hundred feet of bedrock. Availability of ground water is highly variable. Yields commonly range from only 1 to 5 gallons per minute from wells in surficial materials and bedrock, but can be as much as 1,000 gallons per minute from wells in the sand and gravel aquifer underlying the Embarrass River valley. Except over the mineralized zone, ground water in the surficial deposits is a mixed calcium magnesium bicarbonate type. Ground water over the mineralized zone generally has both a greater percentage of sulfate, compared to bicarbonate, and concentrations of copper and nickel greater than 5 micrograms per liter. "Surface-water investigations indicate that the average annual runoff from streams is about 10 inches. Plow characteristics of streams unregulated by industry are similar, with about 60 percent of the annual runoff occurring during snowmelt in April, May, and June. Flood peaks are reduced in the Kawishiwi River and other streams that have surface storage available in onchannel lakes and wetlands. These lakes and wetlands also trap part of the suspended-sediment load. Specific conductance in streams can exceed 250 micromhos per centimeter at 25° Celsius where mine dewatering supplements natural discharge. "Between 85 and 95 percent of the surface water used is for hydroelectric power generation at Winton and thermo-electric power generation at Colby Lakes. Mine dewatering accounts for about 95 percent of the ground-water used. Estimated ground-water discharge to projected copper-nickel mines ranges from less than 25 to about 2,000 gallons per minute, depending on the location and type of mining activity. The introduction of trace metals from future mining to the ground-water system can be reduced if tailings basins and stockpiles are located on material of low permeability, such as till, peat, or bedrock.

Occupational plans of Iowa farm boys

This bulletin reports the findings of an exploratory study of the long-range occupational plans of Iowa farm boys in their senior year of high school. The primary objectives of the study were: (1) to relate the theory of choice to occupational planning, (2) to describe the occupational plans of the boys, (3) to determine the characteristics which differentiate boys who plan to farm from boys who plan nonfarm careers and (4) to appraise the relative importance of factors influencing farm-nonfarm occupational plans. Application of the theory of choice to occupational planning resulted in three general hypotheses to explain why some farm boys plan to farm while others plan nonfarm occupations. These hypotheses involved individual differences in (1) occupational satisfaction functions (preference systems), (2) available resources and (3) the results expected from using given resources in farm and nonfarm employments. Various operational hypotheses derived from the general hypotheses were evaluated on the basis of evidence obtained from a state-wide sample of senior farm boys attending Iowa high schools in rural areas and cities under 25,000 population in the spring of 1959