Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.

In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1.

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK Shifts Mislead Popular Bioisosterism Concepts.

Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pK values are modulated influencing protonation states and bioavailability.

Molecular characterization of Cryptosporidium sp. isolated from northern Alaskan caribou (Rangifer tarandus).

Cryptosporidium sp. was found in 3 out of 49 caribou (Rangifer tarandus) from northern Alaska. Segments of both the 18S ribosomal RNA and the heat shock protein genes were amplified from the caribou isolate and compared with that obtained from an isolate from a wild white-tailed deer (Odocoileus virginianus) in Virginia as well as other species and isolates available from GenBank.

Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings.

Recently an increased echogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD) was demonstrated by transcranial ultrasound (TCS). In this study we set out to compare SN echogenicitiy with disease characteristics (time of onset, duration, toxin exposure) in a large patients sample. Patients' history and exposure to toxins were recorded from 112 PD patients who underwent a thorough neurological examination including assessment of disease stage according to Hoehn and Yahr and CURS (Columbia University Rating Scale).

Relationship of substantia nigra echogenicity and motor function in elderly subjects.

Background: Patients with Parkinson's disease (PD) exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography. Some healthy adults with the same echo characteristics showed a reduced 18fluorodopa uptake on PET, indicating a subclinical alteration of the nigrostriatal system.

Objectives: To determine whether the sonographic phenotype of hyperechogenic SN has any relevance for motor function in elderly subjects and whether an increased echogenicity of the SN is associated with an impaired motor function.

Ostertagia ostertagi challenge of calves vaccinated with Haemonchus placei intestinal homogenate.

The protective capacity of vaccination with Haemonchus placei whole gut homogenate against challenge with the non-blood-feeding nematode Ostertagia ostertagi was evaluated in calves. Ten helminth-free calves were randomly assigned to two groups. Group 1 received 100microg H.

The effectiveness of doramectin pour-on in the control of gastrointestinal nematode infections in cow-calf herds.

Two field studies were conducted in the USA to determine the efficacy of a single strategically-timed dose of doramectin pour-on in the control of gastrointestinal nematodosis in beef cow-calf herds and the resultant effects on calf productivity. One study was carried out between May and October 1996 in a spring-calving herd at a site located in Idaho (ID) and the other between January and July 1997 in a fall-calving herd at a site located in Mississippi (MS). In each study, cow-calf pairs were randomly allotted by sex of calf to pastures and one of two treatment groups (doramectin pour-on at the recommended dose rate of 500 microg/kg body weight or untreated control).

Vaccination of calves with Haemonchus placei intestinal homogenate.

The ability of adult Haemonchus placei intestinal homogenate to confer protection against homologous challenge infection was evaluated. Calves were immunized twice with 100 microg H. placei intestinal protein in 5% dextran-sulfate/PBS (vaccinates) or PBS alone (controls) and were challenged with approximately 3300 infective H.

Persistent activity of doramectin injectable formulation against experimental challenge with Haemonchus placei in cattle.

Two studies were conducted in North America to evaluate the persistent activity of doramectin injectable formulation against experimental challenge with Haemonchus placei. In both studies, calves were randomly assigned to 1 of 4 treatment groups (n = 10 per group) or a larval viability group (n = 2). Calves were treated subcutaneously in the lateral midline of the neck with saline (1 ml/50 kg) on Day 0, or with doramectin (200 mg/kg = 1 ml/50 kg) on Day 0, 7, or 14.

The prevalence of Cryptosporidium and Giardia spp. in fecal samples from free-ranging white-tailed deer (Odocoileus virginianus) in the southeastern United States.

The prevalence of Cryptosporidium sp. and Giardia sp. in fecal samples collected from free-ranging white-tailed deer (Odocoileus virginianus) was determined for animals in Virginia and Mississippi.

Demonstration of shared carbohydrate epitopes in intestinal proteins of some bovine gastrointestinal nematodes.

The presence of shared carbohydrate intestinal epitopes in bovine gastrointestinal nematodes was demonstrated. Proteins were extracted from the intestinal tissue of a laboratory strain of adult Haemonchus placei and used to produce monoclonal antibodies (mAb). Analysis of this detergent extract by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed 7-9 bands ranging from approximately 39 to 298 kDa.

Efficacy of doramectin for treatment of experimentally induced infection with gastrointestinal nematodes in calves.

Objective: To determine the efficacy of injectable doramectin against experimentally induced infections with adult and larval (L4) stages of gastrointestinal nematodes in calves.

Procedures: In each experiment, between 20 (experiments 1 and 2) and 30 (experiment 3) parasite-free yearling calves were selected and allotted to groups of 10/group. All calves received oral inoculation of the following infective larval stages of these nematode species: Cooperia onchophora, C punctata, C zurnabada, Cooperia spp, Haemonchus placei, Nematodirus helvetianus, Oesophagostomum radiatum, Ostertagia ostertagi, Trichostrongylus axei, and T colubriformis.

Epidemiological study of nematode infections in a grazing beef cow-calf herd in Mississippi.

The epidemiology of gastrointestinal nematodes was studied in a spring calving herd in northeast Mississippi. Pregnant, mixed breed beef cows (n = 15) were placed on a 10 ha fescue/bermuda grass pasture from January 1990-February 1992. In both years, calves were born from February-April and were weaned and removed from the pasture in mid-October.

Evidence for arrested development of abomasal nematodes in white-tailed deer.

White-tailed deer (Odocoileus virginianus) obtained from Noxubee National Wildlife Refuge, Noxubee County, Mississippi (USA) during April (n = 3), June (n = 5), September (n = 5), and November (n = 5) 1989, were necropsied for counting and identification of adult and larval stages of abomasal nematodes. Fourth-stage larvae (L4) (n < or = 25) from each deer were randomly selected for measurement of total worm length and width. Adults of four worm species were found: Mazamastrongylus odocoilei, M.

Occurrence and seasonal transmission of hematozoa in wild turkeys.

The occurrence and seasonal patterns of transmission of the blood protozoa of wild turkeys (Meleagris gallopavo silvestris) were studied at Tallahala Wildlife Management Area (TWMA) (Jasper County, Mississippi, USA). Blood smears obtained from wild turkeys in winter, spring and summer, and from sentinel domestic turkeys throughout the year were examined for Haemoproteus meleagridis and Leucocytozoon smithi. Whole blood from wild turkeys captured in summer was subinoculated into malaria-free domestic turkey poults and recipient birds were examined for Plasmodium spp.

Schistosoma mansoni: differences in acetylcholine, dopamine, and serotonin control of circular and longitudinal parasite muscles.

The physiological and pharmacological properties of circular and longitudinal somatic musculature in adult male Schistosoma mansoni were compared using cut muscle sections. Carbachol reduced tone in both circular and longitudinal muscle, but was without effect on circular muscle bathed in high Mg2+, indicating that cholinergic receptors were not associated with circular muscle membrane. 5-Hydroxytryptamine (5-HT) induced rhythmic contractile activity in both sets of muscle.

Schistosoma mansoni: a comparison of male and female muscle physiology.

Surface electrical activity and membrane potentials recorded from male and female Schistosoma mansoni are similar. Surface electrical activity and responses to electrical stimulation are slightly higher in females. Contractures induced by praziquantel, 60 mM K+, ouabain or 5 degrees C are slightly less in females but responses to putative neurotransmitters (5-HT, dopamine and carbachol) are the same in both sexes.