bluuebunny/crossref_metadata_2025 huggingface dataset:
Fracture‐Controlled Ground‐Water Circulation and Well Siting in the Vicinity of Laramie, Wyoming
Authors: Huntoon Peter W. , Lundy Don A.
Published: July 2006

The artesian Casper aquifer, comprised of 700 ft of interbedded limestones and sandstones, currently supplies 70 percent (3.5 Mgal/d) of the municipal‐water needs of Laramie, Wyoming. Large transmissivities occur in fracture zones associated with faults and folds in the area, and water discharges from several springs localized along these structures. Transmissivities in fracture zones are 100 times greater than those in unfractured parts of the aquifer. The overlying Satanka Shale is a regional confining unit even in most areas of fracturing, and is a source of poor quality ground water. Prospecting for new ground‐water supplies near Laramie involves mapping the tectonic structures and drilling into them once they are identified.
Ground‐Water Resource Management in Nebraska
Authors: Fricke Carl A. P. , Pederson Darryll T.
Published: July 2006

In order to regulate the use of ground water, State agencies and local government, together with local public participation, have developed a management policy which is now being implemented in Nebraska. A water‐resource agency, a geological survey, and a local, multi‐county governmental unit are combined with several other governmental units to investigate water problems and guide a variety of vested interests toward a common goal of efficient water‐resource management. The key government document delegating the authority and guiding the agencies is the Nebraska Ground Water Management Act of 1975. This Act specifies a procedure whereby local residents concerned about misuse and depletion of their ground‐water supplies can request that official hearings be held, water‐supply evaluations be made, and consideration be given by the Nebraska Department of Water Resources to establish what is called a “control area.” Designation of a control area allows development and enforcement of methods to deal with the water‐resource problem within that area. The management alternatives provided for by this Act include well spacing, rotation of pumping, allocation of water, and moratoriums on drilling. The Act does not, however, address conjunctive use of surface water and ground water, guidelines for management policies, and rights to artificially stored ground water.
Ground‐Water Pollution by Transfer of Oil Hydrocarbons
Authors: Fried J. J. , Muntzer P. , Zilliox L.
Published: July 2006

An important aspect of the pollution of a phreatic aquifer by hydrocarbons is the oil‐water contact and transfer of soluble substances from the oil into the ground water.

A systematic study of this transfer of matter in a saturated porous medium (initial condition of contact when the impregnation body is submitted to fluctuations of the piezometric level) is performed with an experimental device made up of a porous matrix containing the oil phase, steady and crossed by a unidirectional flow of water. The transfer is very efficient; for all compounds which have been studied, the maximum possible concentration is reached after a distance of the order of 10 cm with specific flow rates greater than those generally encountered in a gravel‐sand aquifer. The selective impoverishment of the oil product with time, due to differences in the solubility of various hydrocarbons, modifies the dissolved phase composition. Downstream of an in‐situ impregnation body, this phenomenon only appears after a constant concentration has been reached for a long time. A source model is thus obtained, where the pollutant massic flow rate is proportional to the flow rate of the water which crosses the impregnation body. Such an initial condition has a fundamental effect on the determination of the contaminated aquifer domain, with the help of the dispersion scheme, with hydrocarbon concentrations evolving according to a general diffusion‐convection law.
USEFULNESS OF WELL REGISTRATION DATA
Authors: Pederson Darryll T.
Published: July 2006

Abstract. This investigation was to determine whether data on irrigation‐well registration forms as reported by well drillers can be used in hydrologic studies. Transmissivity maps were prepared for Hamilton County, Nebraska using only specific capacity values computed from yield and drawdown data, as reported on irrigation well‐registration forms. On one map each control point was the mean of the transmissivity values calculated for all wells in a section. On a second map each control point was the mean of the means for four contiguous sections sharing a common corner. The second map was similar to that of a previously prepared map based on control point values computed from specific capacities of selected wells, test hole logs, and geologic interpretations. These results suggest that reported registration data for a given area have a normal population distribution. In situations where individual data are unverified the data base can be treated as samples of a population where the mean of the means of several samples for adjacent areas is representative of actual field conditions.
GROUND‐WATER MANAGEMENT IN GEORGIA
Authors: Kundell James E.
Published: July 2006

Abstract. Although Georgia receives approximately 50 inches of precipitation annually, concern over water quantity is increasing in this State. Historically, ground‐water problems were associated with major urban‐industrial withdrawals but recent irrigation development in the southwestern portion of the State has attracted attention. Irrigation withdrawals were exempted from the permit requirements of the 1972 Ground Water Use Act. This has led to an inability to manage the resource and questions regarding legal rights to the use of water. Current activities in the State indicate that measures may be taken during the 1980 session of the Georgia General Assembly to enable better management of the State's water resources.
Approximation for Salt‐Water Intrusion in Unconfined Coastal Aquifer
Authors: Panigrahi B. K. , Gupta A. Das , Arbhabhirama A.
Published: July 2006

A numerical model based on a finite difference technique has been developed to analyse and solve the problem of an unconfined coastal aquifer of infinite extent with free surface and interface along with the width of outflow face as unknown boundaries. The problem has been formulated in a complex potential plane and a five‐point operator of a finite difference scheme has been used to reduce the governing flow equation into a set of linear algebraic equations which is solved by the Gauss‐Seidel iterative method with an over‐relaxation factor. Results of the analysis provide a generalised dimensionless plot for assessing the fresh‐water flow to the sea from the known field information of aquifer characteristics and water‐table head landward from the shoreline.
Requirements of State Regulatory Agencies for Monitoring Ground‐Water Quality at Waste Disposal Sites
Authors: Clark Thomas P. , Sabel Gretchen V.
Published: July 2006

A survey of the requirements of State regulatory agencies responsible for monitoring ground‐water quality at waste disposal sites was conducted in order to gain a concise profile of monitoring practices across the country, and also to provide the basis for a monitoring manual to serve as technical background and guidance for the citizens of Minnesota. The survey considered a variety of topics including the regulatory framework for requiring monitoring, chemical parameters analyzed, recommended methods of monitoring well construction and sample collection, laboratory quality control, data interpretation, and post‐operational monitoring requirements.

The survey showed that most State monitoring programs are in their infancy. Many States, however, are beginning to devote serious effort and manpower commitments to the development of monitoring programs, although there is considerable divergence of opinion regarding how these programs should be conducted. Federal legislation establishing minimum performance criteria instead of detailed operating requirements for waste disposal sites will increase the need for sound water monitoring programs at these sites in the future.
Determination of the Location and Connectivity of Fractures in Metamorphic Rock with In‐Hole Tracersa
Authors: Marine I. Wendell
Published: July 2006

In‐hole tracer tests were used in a geohydrologic investigation of metamorphic rock at the Savannah River Plant near Aiken, South Carolina, to locate water‐transmitting fractures and to determine the connectivity of these fractures between boreholes. Only after development of a conceptual model of the fracture occurrence and connection could the proper methods of analysis for the hydraulic parameters be selected.

In‐hole tracers were used to locate fractures in a borehole and supplemented other methods, such as core inspection, geophysical logs, borehole wall imaging techniques, dry drilling, and packer tests. The first three of these do not necessarily investigate fluid‐transmitting fractures.

In the study of the connectivity of fractures between boreholes, the in‐hole tracer techniques supplemented determinations by the rapidity of hydraulic response and the use of between‐well tracer tests.

In hydraulically transmissive rock, fractures were located by changes in the velocity of the tracer pulse in response to adding fluid to the well. In virtually impermeable rock, the movement of the tracer pulse in the rock was normalized to the movement of another tracer pulse in the cased portion of the well because the movement was so slow that direct measurement was difficult. Connectivity of fractures between boreholes was determined by placing an in‐hole tracer in one hole and measuring the movement
Estimating Transmissivity and Well Loss Constant Using Multirate Test Data From a Pumped Well
Authors: Nahm G. Y.
Published: July 2006

Linear regression can be applied to multirate pumping test data from a single pumped well to estimate the constants of the equation . An equation has been derived which enables the values of An at various times to be used to estimate the transmissivity of the aquifer adjacent to the pumped well with due allowance for well loss. An extension of method enables estimation of the order of the storage coefficient.
Details of Hydrochemical Variations in Flowing Wells
Authors: Marsh J. Marcus , Lloyd John W.
Published: July 2006

Due to chemical reactions between steel casing and stored water in capped artesian wells, the pH, Eh, TDS, major and trace ion concentrations and saturation indices can be significantly, but relatedly altered from their aquifer values. To obtain true aquifer water samples, either all the stored water must be flushed from the well or a sampling tube must be used to ensure that the water is taken from within the aquifer. Flushing time can be calculated from well dimensions and best be monitored in the field by measuring temperature and electrical conductivity.

This study has been made of confined wells in a fissured limestone, but the reactions which occur are likely to be common to aquifers of different hydrogeology.
Ground‐Water Modeling: Numerical Modelsa
Authors: Faust Charles R. , Mercer James W.
Published: July 2006

Partial differential equations may be used to describe a large number of problems in ground‐water hydrology. Without a solution, however, these equations are of little value. Only a simplified subset of the general equations can be solved by analytical means, and these often describe idealized situations that are limited in application. Numerical solution of these equations using high speed digital computers offers a logical alternative.
Safe Yield in a Coastal Ground‐Water Regime
Authors: Mull Rolf , Battermanna G.
Published: July 2006

The limiting factors for the, safe yield in the investigated coastal area were sea water along the coastline and saline water at about 250 m below sea level. Both types of salt water will intrude into existing wells, when the potential heads are changed sufficiently by increasing pumping. Besides this, the recharge rate due to precipitation affects the potential head.

In a hilly central part of the region, water infiltrates into the ground, and seeps to the saturated zone where it flows some kilometers to flat marshy regions near the coast and estuaries. There it comes up to drainage systems near the land surface (long cycle).

In the marshy region the infiltrated water exfiltrates into drains and ditches after a short passage of some meters in the upper zone of the aquifer (short cycle).

The calibration of a digital ground‐water model gave the existing ground‐water budget. The prognostication of the safe yield was based on these results.

The most interesting problem of model calculations was to take into consideration the dependence of the recharge rate on the depth of the ground‐water table below the land surface. If the ground‐water level is lowered by pumping below the drainage system, the short cycle will be interrupted. The downward seeping water flows within a saturated zone to the wells and affects the potential head. The greater the drawdown, the greater is the recharge rate. The depression of the water table by pumping is compensated up to a certain degree.
The Effect of Flyash Disposal on a Shallow Ground‐Water System
Authors: Cherkauer Douglas S.
Published: July 2006

At a flyash landfill in southeastern Wisconsin, dry ash has been placed directly in contact with a shallow sand and gravel aquifer. Substantial modification of ground‐water quality has occurred primarily by sulfates, calcium and magnesium. However, after eight years, the contamination has spread less than 200 meters from the site in a permeable aquifer. In addition, toxic metals contained in the ash have proven quite immobile in the ground water. Fortuitous location of the disposal site in alkaline sediment upflow from ground‐water discharge in a marsh appears to have limited the extent of contamination.
Horizontal Anisotropy Determined by Pumping in Two Powder River Basin Coal Aquifers, Montana
Authors: Stoner Jeffrey D.
Published: July 2006

Hydraulic anisotropic behavior was determined for the Sawyer‐A and Anderson coal aquifers (Tongue River Member of Paleocene Fort Union Formation) by five‐well and four‐well aquifer tests, respectively. The average maximum hydraulic conductivity of 0.65 m/d (2.13 ft/d) for the Sawyer‐A coal aquifer bears N. 85° E. The average minimum hydraulic conductivity, which is perpendicular to the maximum, is 0.26 m/d (0.85 ft/d). Aquifer heterogeneity in the form of poorly developed coal cleat is believed to be responsible for a wide range of principal‐axis orientations determined by a five‐well test performed on the Sawyer‐A coal aquifer. The maximum hydraulic conductivity of the Anderson coal aquifer is 0.20 m/d (0.66 ft/d) and bears N. 32° W. The minimum hydraulic conductivity is 0.07 m/d (0.23 ft/d). When coal cleat orientation and development are unknown, a five‐well aquifer test proves more beneficial than a four‐well test in analyzing the reliability of the results.

Well storage and aquifer dewatering affected the drawdowns of the pumped well during both tests. However, such effects were minimal, as indicated by drawdowns in observation wells at a distance as small as 13m (44 ft) from the pumped well. Average hydraulic conductivity determined from drawdowns observed at the pumped wells alone were lower than average values determined from a multiple‐well analysis.
Preliminary Evaluation of an Alternate Electrode Array for Use in Shallow‐Subsurface Electrical Resistivity Studies
Authors: Carringtona Thomas J. , Watson Don A.
Published: July 2006

Nine electrode arrays were examined under controlled laboratory conditions to evaluate their relative efficiency with regard to time and space requirements, and with regard to effective prediction of subsurface conditions in electrical resistivity surveys. Of the nine investigated, the Wenner and a modification thereof (“Modified Wenner”) were selected for field testing and comparison. To a limited extent the Schlumberger array also was compared.

Field testing of the three chosen arrays suggested the superiority of the Modified Wenner over the Wenner array in reliability of data obtained under most conditions examined, speed of completion of a survey and minimal straight‐line distance required for a 100‐foot (30.5‐meter) depth survey. Insufficient data were gathered with the Schlumberger array for proper comparison with the other two arrays.

Subsurface conditions predicted by resistivity data were confirmed by subsurface projections of geological features suggested by previous surficial mapping, by drillers'records and by seismic refraction data.
The Relationship Between Fracture Traces and Joints in a Tertiary Basin, Southwest Montana
Authors: Krothe Noel C. , Bergeron Marcel P.
Published: July 2006

The relationship between fracture traces mapped on aerial photographs and joints mapped in the field were examined for a synclinal basin, near Three Forks, Montana, Fracture traces mapped in the southern half of the Milligan Canyon area by stereoscopic examination of aerial photographs show a predominant east‐west and north‐south orientation.

A total of 4,675 joint orientation measurements made in the field also showed predominant north‐south and east‐west orientations. The similarity suggests that mapped fracture traces reflect areas of joint and fracture concentrations in the subsurface and may be a valuable water exploration tool in Tertiary basins of Montana.
Waste Heat Balance in Aquifers Calculated by a Computer Programme
Authors: Kley Wolfram , Heekmann Winfried
Published: July 2006

Because of the feeding of waste heat over many years into the aquifers of the city of Cologne, Federal Republic of Germany, a subsurface energy resource has been built up. By analyzing the temperature measurements in ground water by means of a computer programme the isolines of the energy resource and of the recoverable amount of heat can be determined and represented. Practical application of the results of these investigations is important for the planning and design of heat pump units in agglomeration areas. In conclusion, prognoses on future temperature distribution in aquifers of the city of Cologne are made.
Hydrogeology of the Sierra Nevada Foothill Lineament Near Oakhurst, California
Authors: Mack Seymour , Schmidt Kenneth D.
Published: July 2006

Thirty‐three wells and two springs yielding high chloride water from granitic rocks define a northwesttrending lineament, which extends for 60 miles (100 km) along the western Sierra Nevada foothills of Fresno and Madera Counties. Geochemical evidence indicates that many of the constituents in this water are marine connate in origin. However, the connate water has been strongly diluted with meteoric water. The connate water is believed to have been derived from Paleozoic and early Mesozoic marine clastic rocks (now metamorphosed) in the Sierra Nevada. The lineament marks the location where marine connate water has migrated upward from these rocks along an eastward‐dipping fault zone. A capping of granitic rocks has enhanced the persistence of this connate water for millions of years. The lineament may be structurally related to the Oakhurst‐Fine Gold fault zone, which it parallels for approximately 15 miles (25 km). There is a remarkable correlation in the Oakhurst area between wells yielding high‐chloride water and fracture trends determined from aerial photographs. High chloride ground water is present only in topographically low areas, where little flushing by meteoric water has been possible.
Numerical Simulation of Potentiometric Surface Changes Caused by a Proposed Open‐Pit Anthracite Mine
Authors: Bair E. Scott , Parizek Richard R.
Published: July 2006

The Trescott, Pinder, Larson (Trescott and others, 1976) finite‐difference flow model was modified and used to simulate potentiometric surface changes caused by the development of a proposed open‐pit anthracite mine. The modifications to the program code were made to account for site‐specific hydrogeologic conditions and to simulate the mining operation. In order to account for vertical changes in hydraulic conductivity caused by underground mine voids, the coefficient subroutine (COEF) was modified to permit the value of hydraulic conductivity to vary with depth. The lateral growth and deepening of the mine were simulated by changing the data input subroutine (DATAI) to allow the number, location, and hydraulic head of constant‐head nodes to vary with the time period. The mass balance subroutine (CHECKI) was modified to print out the flux into each constant‐head node at the end of each time period, thereby permitting calculation of changes in the rate of ground‐water flow into the mine.

Site‐specific values of hydraulic conductivity, specific yield, aquifer recharge, streambed permeability, and hydraulic head initially were used in the modeling studies. Input parameter values were adjusted within the range of established field values during steady‐state model calibration. It was not possible to calibrate the transient model because the mining operation was in the planning stage and, therefore, no historical data existed. Nonetheless, transient simulations using the adjusted input parameter values and the simulated hydraulic head values were made to show that it is possible to model potentiometric surface changes caused by ground‐water flow into an open‐pit mine. These simulations predicted that, after eight years of mining, a cone of depression approximately 20,000‐feet long, 8000‐feet wide, and 1000‐feet deep would form around the proposed mine. The results of the transient simulations were used in a preliminary manner to assess the potential hydrogeologic impact of the proposed mining operation.
Yield Verification of a Dolomite Aquifer in Northeast Illinois
Authors: Sasman Robert T. , Schicht Richard J. , Benson Curtis R. , Ludwigs R. Scott
Published: July 2006

Pumpage from shallow aquifers, primarily dolomite bedrock, in northeastern Illinois has exceeded estimates of ground‐water recharge in extensive areas creating concern that ground‐water recharge estimates are too low. Pumpage increased 92 percent during the period 1966‐1978 and was 61.7 million gallons per day (2.33 × 108 liters/day) during 1978. During the period 1966‐1979 water level declines exceeded 30 feet (9.14 meters) in some areas. Based on a ground‐water budget study, it was determined that recharge estimates were in the right order of magnitude and pumpage in excess of recharge was balanced by water taken out of storage from the shallow aquifers. A specific yield of 0.017 was determined for the dolomite bedrock aquifer based on the ground‐water budget study.
An Aquifer Simulation Program for Micro‐Based Processors
Authors: Briz‐Kishore B. H. , Avadhanulu R.V.S.S.
Published: July 2006

A generalized aquifer simulation program is designed and developed to handle problems connected with different kinds of complex ground‐water systems on microprocessors. The characteristic aspect of this program, involving the “Strongly Implicit Procedure” is that it requires only 10K bytes of memory for the generated code.

Using this program, the effect of pumping on an aquifer can be studied for multiple pumping periods and predictions or observations can be scrutinized at various time steps within each pumping period. The program can also handle conversion problems between confined and water‐table aquifers under leaky or nonleaky states along with the effects of evapotranspiration, constant recharge or discharge boundaries. The utility and precision of the program have been tested using a sample problem quoted by Trescott et al. (1976).
Geohydrologic Models of the Houston District, Texas
Authors: Jorgensen Donald G.
Published: July 2006

The major water‐bearing units in the Houston district are the Chicot and Evangeline aquifer systems. Both systems consist of discontinuous layers of unconsolidated sand (aquifers) separated by clay layers.

Extensive pumping has caused large declines of potentiometric surfaces in and around Houston. The declines have caused both the compaction of clay layers, which has resulted in land‐surface subsidence, and the movement of salt water towards Houston.

During the early 1960's, an electric analog model of the district was made. The model simulated water‐level declines; but more importantly, the model indicated that the available data and conceptual model of the hydrologic system, consisting of two aquifers, were not totally adequate to allow simulation of the ground‐water systems.

During the early 1970's, a second electric analog was built. The second model used new data and a conceptual model consisting of two aquifer systems simulated water‐level declines quite accurately, but the model was unable to accurately simulate the spatial distribution of water yielded from clay storage.

A digital model was then developed during 1979 to simulate the hydrology of the district. The digital model used five layers and accurately simulated the hydraulic heads in both aquifer systems and land‐surface subsidence.
Characterization of a Contaminant Plume in Ground Water, Meredosia, Illinois
Authors: Naymik Thomas G. , Barcelona Michael J.
Published: July 2006

Aspects of a nine‐month characterization of the physical‐chemical dynamics of a dissolved inorganic fertilizer plume in a shallow sand and gravel aquifer are reported. The work was undertaken to establish the extent of ground‐water contamination due to extremely high levels of total ammonia (>2,000 mg L−1) and to provide a basis for remedial action.

The results from a numerical solute transport model showed the plume of contaminated ground water persisted at steady‐state conditions within the study site. This conclusion is supported by a comparison of the time of source emplacement (three years) to the calculated requirement of approximately one year for the plume at the field location to achieve a steady‐state configuration. Simulations suggested once the source was removed, about 420 days would be required to naturally flush the contaminant plume from the site.

Chemical equilibrium calculations demonstrate that phosphate and carbonate mineral equilibria control calcium solubility in contaminated ground water. The most probable natural sink for ammonia removal from the plume is by the activity of nitrifying microorganisms, presumably well‐acclimated to the extreme conditions.
Well Vulnerability: A Quantitative Approach for Source Water Protection
Authors: Frind E.O. , Molson J.W. , Rudolph D.L.
Published: July 2006

The concept of vulnerability of drinking water sources is reviewed, and a quantitative approach for assessing well vulnerability for complex three‐dimensional ground water systems is developed. The approach focuses on the relative expected impact of potential contaminant sources at unknown locations within a well capture zone, providing relative measures of intrinsic well vulnerability, including the expected times of arrival of a contaminant, the dispersion‐related reduction in concentration, the time taken to breach a certain quality objective, and the corresponding exposure times. Thus, the result of the analysis includes the usual advective travel time information used in conventional wellhead protection analysis, plus a set of selected quantitative measures expressing the expected impact. The technique is based on adjoint theory and combines forward‐ and backward‐in‐time transport modeling using a standard numerical flow and transport code. The methodology is demonstrated using the case study of a complex glacial multiaquifer system in Ontario. The new approach will be useful in helping water managers develop more physically based and quantitative wellhead protection strategies.
An Assessment of Aquifer Storage Recovery Using Ground Water Flow Models
Authors: Lowry Christopher S. , Anderson Mary P.
Published: July 2006

Owing to increased demands on ground water accompanied by increased drawdowns, technologies that use recharge options, such as aquifer storage recovery (ASR), are being used to optimize available water resources and reduce adverse effects of pumping. In this paper, three representative ground water flow models were created to assess the impact of hydrogeologic and operational parameters/factors on recovery efficiency of ASR systems. Flow/particle tracking and solute transport models were used to track the movement of water during injection, storage, and recovery. Results from particle tracking models consistently produced higher recovery efficiency than the solute transport models for the parameters/properties examined because the particle tracking models neglected mixing of the injected and ambient water. Mixing between injected and ambient water affected recovery efficiency. Results from this study demonstrate the interactions between hydrogeologic and operational parameters on predictions of recovery efficiency. These interactions are best simulated using coupled numerical ground water flow and transport models that include the effects of mixing of injected water and ambient ground water.
Reducing Long‐Term Remedial Costs by Transport Modeling Optimization
Authors: Becker David , Minsker Barbara , Greenwald Robert , Zhang Yan , Harre Karla , Yager Kathleen , Zheng Chunmiao , Peralta Richard
Published: July 2006

The Department of Defense (DoD) Environmental Security Technology Certification Program and the Environmental Protection Agency sponsored a project to evaluate the benefits and utility of contaminant transport simulation‐optimization algorithms against traditional (trial and error) modeling approaches. Three pump‐and‐treat facilities operated by the DoD were selected for inclusion in the project. Three optimization formulations were developed for each facility and solved independently by three modeling teams (two using simulation‐optimization algorithms and one applying trial‐and‐error methods). The results clearly indicate that simulation‐optimization methods are able to search a wider range of well locations and flow rates and identify better solutions than current trial‐and‐error approaches. The solutions found were 5% to 50% better than those obtained using trial‐and‐error (measured using optimal objective function values), with an average improvement of ∼20%. This translated into potential savings ranging from $600,000 to $10,000,000 for the three sites. In nearly all cases, the cost savings easily outweighed the costs of the optimization. To reduce computational requirements, in some cases the simulation‐optimization groups applied multiple mathematical algorithms, solved a series of modified subproblems, and/or fit “meta‐models” such as neural networks or regression models to replace time‐consuming simulation models in the optimization algorithm. The optimal solutions did not account for the uncertainties inherent in the modeling process. This project illustrates that transport simulation‐optimization techniques are practical for real problems. However, applying the techniques in an efficient manner requires expertise and should involve iterative modification to the formulations based on interim results.
Searching for New Antimalarial Therapeutics amongst Known Drugs
Authors: Weisman Jennifer L. , Liou Ally P. , Shelat Anang A. , Cohen Fred E. , Kiplin Guy R. , DeRisi Joseph L.
Published: July 2006

The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug‐like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high‐throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.
Structural Evaluation of a Novel Pro‐apoptotic Peptide Coupled to CNGRC Tumor Homing Sequence by NMR
Authors: Sandoval Cristina M. , Geierstanger Bernhard H. , Fujimura Satoshi , Balatbat Calvin , Williams Taylor , De Unamuno Julio , Whiles‐Lillig Jennifer A. , Ellerby Lisa M. , Michael Ellerby H. , Jennings Patricia , Plesniak Leigh A.
Published: July 2006

Hunter‐killer peptides (HKPs) are synthetic peptides that target specific cell types for apoptosis. These studies report functional and structural characteristics of HKP9, an hunter‐killer peptide that specifically targets tumor vasculature with a new apoptotic sequence. Vesicle leakage experiments were performed as a model for membrane perturbing activity. Placement of the homing sequence reduces both cell toxicity and vesicle leakage activity. NMR studies elucidate the conformation and orientation of HKP9 in micelles. The positively charged end of the HKP9 killing sequence is solvent exposed; however, the central portion of the peptide is helical and buried in dodecylphosphorylcholine micelles. The homing sequence is less solvent exposed than in a previously reported tumor‐homing peptide. The results suggest that solvent accessibility of the homing sequence should be considered in design of future peptides.
Design of a Peptibody Consisting of the Antimicrobial Peptide dhvar5 and a llama Variable Heavy‐chain Antibody Fragment
Authors: Szynol A. , De Haard J. J. W. , Veerman E. C. , De Soet J. J. , Van Nieuw Amerongen A. V.
Published: July 2006

Immunoconjugates have been widely studied as potential therapeutics for infectious diseases to direct unspecific antimicrobials to pathogens. In this study, the recombinant approach was used for expression of the immunoconjugate composed of the variable domain of a llama heavy‐chain antibody (VHH) against Streptococcus mutans and dhvar5, a synthetic antimicrobial peptide. Before cloning, the impact of the elongation of the peptide termini on its biological activity was evaluated by chemical synthesis of the N‐ or C‐termini extended dhvar5 peptides. As the elongation of the C‐terminus had a greater influence on decline of the antimicrobial activity, the N‐terminal fusion was designed. To promote in vivo release of the active peptide, a factor Xa cleavage site was inserted between VHH and dhvar5. Propagation of transformed Escherichia coli with the constructed plasmid was only possible in the absence of isopropyl β‐D‐thiogalactoside (IPTG). Although these data demonstrate that the diminished antimicrobial activity of dhvar5 by the N‐terminal fusion to VHH was not sufficient for the protection of the bacterial host cells against the peptide lethal effect, an insight into propeptides biological activities may be beneficial not only for new and more successful rearrangement of the VHH–dhvar5 immunoconjugate construct, but also design of the other recombinant molecules composed of peptides toxic to host cells.
A Kinase‐focused Compound Collection: Compilation and Screening Strategy
Authors: Sun Dongyu , Chuaqui Claudio , Deng Zhan , Bowes Scott , Chin Donovan , Singh Juswinder , Cullen Patrick , Hankins Gretchen , Lee Wen‐Cherng , Donnelly Jason , Friedman Jessica , Josiah Serene
Published: July 2006

Lead identification by high‐throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase‐focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape‐based virtual screening and a receptor‐based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry‐picked from an existing high‐throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase‐focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase‐focused compound collection for lead identification has been added to existing strategies.
Design and Synthesis of anα1a‐Adrenergic Receptor Subtype‐Selective Antagonist from BE2254
Authors: Chiu George , Gluchowski Charles , Forray Carlos
Published: July 2006

Anα1a‐adrenoceptor‐selective antagonist has the potential to be a new benign prostatic hyperplasia drug with reduced side‐effects. Modification of the non‐selective antagonist BE2254 led to the development of a series of tetralin analogs. Evaluation of these compounds in cloned humanα1‐adrenoceptors resulted in the discovery of an analog that showed selectivity toward the humanα1a‐adrenergic receptor subtype. The compound also showed moderate potency to block human prostate muscle contraction.
n

-Point Asperity Model for Contact Between Nominally Flat Surfaces
Authors: Hariri A. , Zu J. W. , Ben Mrad R.
Published: July 2006

For several decades, asperities of nominally flat rough surfaces were considered to be points higher than their immediate neighbors. Recently, it has been recognized that this model is incorrect. To address the issue, a new multiple-point asperity model, called the n-point asperity model, is introduced in this paper. In the new model, asperities are composed of n neighboring sampled points with n-2 middle points being above a certain level. When the separation between two surfaces decreases, new asperities with higher number of sample points, n, will come into existence. Based on the above model, the height and curvature of n-point asperities are defined and their distributions are found. The model is developed for Gaussian surfaces and for the general case of an autocorrelation function (ACF). As a case study, the exponential ACF is applied to the new model, which is shown to produce remarkably good agreement with measurements from real and simulated surfaces.
Monitoring of Lubricant Film Failure in a Ball Bearing Using Ultrasound
Authors: Zhang Jie , Drinkwater Bruce W. , Dwyer-Joyce Rob S.
Published: July 2006

A lubricant-film monitoring system for a conventional deep groove ball bearing (type 6016, shaft diameter 80 mm, ball diameter 12.7 mm) is described. A high-frequency (50 MHz) ultrasonic transducer is mounted on the static outer raceway of the bearing. The transducer is focused on the ball-raceway interface and used to measure the reflection coefficient of the lubricant in the “contact” ellipse between bearing components. The reflection coefficient characterizes the lubricant film and can be used to calculate its thickness. An accurate triggering system enables multiple reflection measurements to be made as each lubricated contact moves past the measurement location. Experiments are described in which bearings were deliberately caused to fail by the addition of acetone, water, and sand to the lubricant. The ultrasonic reflection coefficient was monitored as a function of time as the failure occurred. Also monitored were the more standard parameters, temperature and vibration. The results indicate that the ultrasonic measurements are able to detect the failures before seizure. It is also observed that, when used in parallel, these monitoring techniques offer the potential to diagnose the failure mechanism and hence improve predictions of remaining life.
Anaphase Inactivation of the Spindle Checkpoint
Authors: Palframan William J. , Meehl Janet B. , Jaspersen Sue L. , Winey Mark , Murray Andrew W.
Published: July 2006

The spindle checkpoint delays cell cycle progression until microtubules attach each pair of sister chromosomes to opposite poles of the mitotic spindle. Following sister chromatid separation, however, the checkpoint ignores chromosomes whose kinetochores are attached to only one spindle pole, a state that activates the checkpoint prior to metaphase. We demonstrate that, in budding yeast, mutual inhibition between the anaphase-promoting complex (APC) and Mps1, an essential component of the checkpoint, leads to sustained inactivation of the spindle checkpoint. Mps1 protein abundance decreases in anaphase, and Mps1 is a target of the APC. Furthermore, expression of Mps1 in anaphase, or repression of the APC in anaphase, reactivates the spindle checkpoint. This APC-Mps1 feedback circuit allows cells to irreversibly inactivate the checkpoint during anaphase.
Induction of Multiple Prophages from a Marine Bacterium: a Genomic Approach
Authors: Chen Feng , Wang Kui , Stewart Jeneen , Belas Robert
Published: July 2006

Approximately 70% of sequenced bacterial genomes contain prophage-like structures, yet little effort has been made to use this information to determine the functions of these elements. The recent genomic sequencing of the marine bacterium
Silicibacter
sp. strain TM1040 revealed five prophage-like elements in its genome. The genomes of these prophages (named prophages 1 to 5) are approximately 74, 30, 39, 36, and 15 kb long, respectively. To understand the function of these prophages, cultures of TM1040 were treated with mitomycin C to induce the production of viral particles. A significant increase in viral counts and a decrease in bacterial counts when treated with mitomycin C suggested that prophages were induced from TM1040. Transmission electron microscopy revealed one dominant type of siphovirus, while pulsed-field gel electrophoresis demonstrated two major DNA bands, equivalent to 35 and 75 kb, in the lysate. PCR amplification with primer sets specific to each prophage detected the presence of prophages 1, 3, and 4 in the viral lysate, suggesting that these prophages are inducible, but not necessarily to the same level, while prophages 2 and 5 are likely defective or non-mitomycin C-inducible phages. The combination of traditional phage assays and modern microbial genomics provides a quick and efficient way to investigate the functions and inducibility of prophages, particularly for a host harboring multiple prophages with similar sizes and morphological features.
Effect of Drug Transporter Genes on Cysteine Export and Overproduction in
Escherichia coli
Authors: Yamada Satoshi , Awano Naoki , Inubushi Kyoko , Maeda Eri , Nakamori Shigeru , Nishino Kunihiko , Yamaguchi Akihito , Takagi Hiroshi
Published: July 2006

l
-Cysteine is an important amino acid in terms of its industrial applications. We previously found a marked production of
l
-cysteine from glucose in recombinant
Escherichia coli
cells expressing an altered
cysE
gene encoding feedback inhibition-insensitive serine acetyltransferase. Also, a lower level of cysteine desulfhydrase (CD) activity, which is involved in
l
-cysteine degradation, increased
l
-cysteine productivity in
E. coli
. The use of an
l
-cysteine efflux system could be promising for breeding
l
-cysteine overproducers. In addition to YdeD and YfiK, which have been reported previously as
l
-cysteine exporter proteins in
E. coli
, we analyzed the effects of 33 putative drug transporter genes in
E. coli
on
l
-cysteine export and overproduction. Overexpression of the
acrD
,
acrEF
,
bcr
,
cusA
,
emrAB
,
emrKY
,
ybjYZ
, and
yojIH
genes reversed the growth inhibition of
tnaA
(the major CD gene)-disrupted
E. coli
cells by
l
-cysteine. We also found that overexpression of these eight genes reduces intracellular
l
-cysteine levels after cultivation in the presence of
l
-cysteine. Amino acid transport assays showed that Bcr overexpression conferring bicyclomycin and tetracycline resistance specifically promotes
l
-cysteine export driven by energy derived from the proton gradient. When a
tnaA
-disrupted
E. coli
strain expressing the altered
cysE
gene was transformed with a plasmid carrying the
bcr
gene, the transformant exhibited more
l
-cysteine production than cells carrying the vector only. A reporter gene assay suggested that the
bcr
gene is constitutively expressed at a substantial level. These results indicate that the multidrug transporter Bcr in the major facilitator family is involved in
l
-cysteine export and overproduction in genetically engineered
E. coli
cells.
The 3′ CCACCA Sequence of tRNA
Ala
(UGC) Is the Motif That Is Important in Inducing Th1-Like Immune Response, and This Motif Can Be Recognized by Toll-Like Receptor 3
Authors: Wang Zhijun , Xiang Li , Shao Junjie , Yuan Zhenghong
Published: July 2006

In this article, the immunogenicity of tRNA and the recognition of tRNA by Toll-like receptors (TLRs) are analyzed. Analyses of the effects of different tRNA
Ala
(UGC) fragments (tRNA
Ala
1-76 [corresponding to positions 1 through 76], tRNA
Ala
26-76, tRNA
Ala
40-76, tRNA
Ala
62-76, tRNA
Ala
1-70, tRNA
Ala
26-70, tRNA
Ala
40-70, and tRNA
Ala
62-70) on the immune responses of hepatitis B surface antigen (HBsAg) were performed with BALB/c mice. Results show that tRNA
Ala
1-76, tRNA
Ala
26-76, tRNA
Ala
40-76, and tRNA
Ala
62-76 adjuvants not only induced stronger T helper (Th) 1 immune responses but also cytotoxic-T-lymphocyte (CTL) responses relative to tRNA
Ala
1-70, tRNA
Ala
26-70, tRNA
Ala
40-70, and tRNA
Ala
62-70 adjuvants in HBsAg immunization. A deletion of the D loop (tRNA
Ala
26-76), anticodon loop (tRNA
Ala
40-76), or TψC (tRNA
Ala
62-76) loop of tRNA
Ala
(UGC) does not significantly decrease the adjuvant characteristic of tRNA
Ala
(UGC). However a deletion of the 3′-end CCACCA sequence (tRNA
Ala
1-70, tRNA
Ala
26-70, tRNA
Ala
40-70, and tRNA
Ala
62-70) of tRNA
Ala
(UGC) significantly decreased the adjuvant characteristic in Th1 and CTL immune responses. Moreover, the recognitions of different tRNA
Ala
(UGC) fragments by TLR3, TLR7, TLR8, and TLR9 were analyzed. Results show that a deletion of the 3′ CCACCA sequence of tRNA
Ala
(UGC) significantly decreased the recognition by TLR3. We concluded that the 3′ CCACCA sequence of tRNA
Ala
(UGC) is the important motif to induce Th1 and CTL responses and this motif can be effectively recognized by TLR3.