Biomedical subjects

S Arthurs

Publications and source records attributed to S Arthurs.

7 recordsLinked to original sources

PubMed2004

An analysis of using entomopathogenic nematodes against above-ground pests.

Applications of entomopathogenic nematodes in the families Steinernematidae and Heterorhabditidae have traditionally been targeted against soil insects. Nonetheless, research over the last two decades highlights the potential of such agents against above-ground pests under certain circumstances. A general linear model was used to test for patterns in efficacy among 136 published trials with Steinernema carpocapsae Weiser, the most common species applied against foliar and other above-ground pests. The focus was on field and greenhouse assessments, rather than laboratory assays where relevant ecological barriers to infection are typically removed. The model showed differences in nematode treatment efficacy depending on the pests' target habitat (bore holes > cryptic foliage > exposed foliage) and trial location (greenhouse > field studies). Relative humidity and temperature during and up to 8 h post-application were also predicted to influence rates of nematode infection obtained. Conversely, spray adjuvants (both wetting agents and anti-desiccants) and nematode dosage applied (both concentration and use of consecutive applications 3-4 days apart) did not explain a significant amount of variance in nematode performance. With reference to case studies the model is used to discuss the relative importance of different factors on nematode efficacy and highlight priorities for workers considering using entomopathogenic nematodes to target pests in novel environments.

Agriculture↗

PubMed2001

Hierarchy of simulation models in predicting molecular recognition mechanisms from the binding energy landscapes: structural analysis of the peptide complexes with SH2 domains.

Computer simulations using the simplified energy function and simulated tempering dynamics have accurately determined the native structure of the pYVPML, SVLpYTAVQPNE, and SPGEpYVNIEF peptides in the complexes with SH2 domains. Structural and equilibrium aspects of the peptide binding with SH2 domains have been studied by generating temperature-dependent binding free energy landscapes. Once some native peptide-SH2 domain contacts are constrained, the underlying binding free energy profile has the funnel-like shape that leads to a rapid and consistent acquisition of the native structure. The dominant native topology of the peptide-SH2 domain complexes represents an extended peptide conformation with strong specific interactions in the phosphotyrosine pocket and hydrophobic interactions of the peptide residues C-terminal to the pTyr group. The topological features of the peptide-protein interface are primarily determined by the thermodynamically stable phosphotyrosyl group. A diversity of structurally different binding orientations has been observed for the amino-terminal residues to the phosphotyrosine. The dominant native topology for the peptide residues carboxy-terminal to the phosphotyrosine is tolerant to flexibility in this region of the peptide-SH2 domain interface observed in equilibrium simulations. The energy landscape analysis has revealed a broad, entropically favorable topology of the native binding mode for the bound peptides, which is robust to structural perturbations. This could provide an additional positive mechanism underlying tolerance of the SH2 domains to hydrophobic conservative substitutions in the peptide specificity region.

Binding Sites↗

PubMed2001

Effects of temperature and relative humidity on sporulation of Metarhizium anisopliae var. acridum in mycosed cadavers of Schistocerca gregaria.

The effects of relative humidity (RH) and temperature on the sporulation of Metarhizium anisopliae var. acridum on mycosed cadavers of desert locust, Schistocerca gregaria, were assessed in the laboratory. Quantitative assessments of conidial production over 10 days under constant conditions showed that sporulation was optimized at RH > 96% and at temperatures between 20 and 30 degrees C. Under both these conditions >10(9) conidia/cadaver were produced. At 25 degrees C, conidial yield was maximized under conditions in which cadavers remained in contact with damp substrate. Relatively little sporulation occurred at 15 degrees C (< 3 x 10(7) conidia/cadaver) and 40 degrees C (< 4 x 10(6) conidia/cadaver) and no sporulation occurred at 10 or 45 degrees C. Following incubation, conidial yield was closely related to the water content of locust cadavers. In separate tests, locust cadavers were incubated for 10 days under diurnally fluctuating temperature and RH that comprised favorable (25 degrees C/100% RH) alternating with unfavorable (40 degrees C/80% RH) conditions for sporulation. In this case, fewer conidia were produced compared with cadavers that were incubated under the favorable conditions for an equal period cumulatively but were not periodically exposed to unfavorable conditions. However, this reduced sporulation observed with the fluctuating condition was not observed when cadavers were similarly incubated under favorable/unfavorable conditions of temperature but were not periodically exposed to the low RH condition. This result implies that sporulation is a dynamic process, dependent not only on periodic exposure to favorable RH but also on the interrelation of this with low RH. Associated tests and the monitoring of changes in cadaver weights imply that the mechanism driving the reduced sporulation under fluctuating RH is the net water balance of cadavers, i.e. the cumulative ability of the fungus/cadaver to adsorb water necessary for sporulation at high RH is restricted by water loss associated with intermittent exposure to a low RH. The duration of daily exposure to high humidity appears to be a crucial constraint to the recycling ability of M. anisopliae var. acridum.

Animals↗

PubMed2000

Deciphering common failures in molecular docking of ligand-protein complexes.

Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as 'soft' and 'hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.

Crystallography↗

PubMed1999

Local anesthesia for prostate brachytherapy.

PURPOSE: To demonstrate the technique and feasibility of prostate brachytherapy performed with local anesthesia only. METHODS AND MATERIALS: A 5 by 5 cm patch of perineal skin and subcutaneous tissue is anesthetized by local infiltration of 10 cc of 1% lidocaine with epinephrine, using a 25-gauge 5/8-inch needle. Immediately following injection into the subcutaneous tissues, the deeper tissues, including the pelvic floor and prostate apex, are anesthetized by injecting 15 cc lidocaine solution with approximately 8 passes of a 20-gauge 1.0-inch needle. Following subcutaneous and peri-apical lidocaine injections, the patient is brought to the simulator suite and placed in leg stirrups. The transrectal ultrasound (TRUS) probe is positioned to reproduce the planning images and a 3.5- or 6.0-inch, 22-gauge spinal needle is inserted into the peripheral planned needle tracks, monitored by TRUS. When the tips of the needles reach the prostatic base, about 1 cc of lidocaine solution is injected in the intraprostatic track, as the needle is slowly withdrawn, for a total volume of 15 cc. The implants are done with a Mick Applicator, inserting and loading groups of two to four needles, so that a maximum of only about four needles are in the patient at any one time. During the implant procedure, an additional 1 cc of lidocaine solution is injected into one or more needle tracks if the patient experiences substantial discomfort. The total dose of lidocaine is generally limited to 500 mg (50 ml of 1% solution). RESULTS: To date, we have implanted approximately 50 patients in our simulator suite, using local anesthesia. Patients' heart rate and diastolic blood pressure usually showed moderate changes, consistent with some discomfort. The time from first subcutaneous injection and completion of the source insertion ranged from 35 to 90 minutes. Serum lidocaine levels were below or at the low range of therapeutic. There has been only one instance of acute urinary retention in the patients treated so far, and no unplanned admissions to the hospital or need to reschedule a patient to be implanted under general or spinal anesthesia. CONCLUSIONS: The substitution of local anesthesia has facilitated rapid introduction of a high-volume brachytherapy program at an institution that previously had none, without requiring the allocation of significant operating room time. Although the patients reported here were implanted without conscious sedation, we are starting to try various sedatives and analgesics for patients who we anticipate will have substantial anxiety with the procedure.

Adrenergic Agonists↗

PubMed1999

Thermodynamics and kinetics of ligand-protein binding studied with the weighted histogram analysis method and simulated annealing.

The thermodynamics of ligand-protein molecular recognition is investigated by the energy landscape approach for two systems: methotrexate(MTX)--dihydrofolate reductase(DHFR) and biotin-streptavidin. The temperature-dependent binding free energy profile is determined using the weighted histogram analysis method. Two different force fields are employed in this study: a simplified model of ligand-protein interactions and the AMBER force field with a soft core smoothing component, used to soften the repulsive part of the potential. The results of multiple docking simulations are rationalized from the shape of the binding free energy profile that characterizes the thermodynamics of the binding process.

Biotin↗

PubMedDate not supplied

Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.

The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.

Animals↗