Inhibitors of hepatitis C virus NS3.4A protease 2. Warhead SAR and optimization

The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.     

Inhibitors of hepatitis C virus NS3.4A protease 1. Non-charged tetrapeptide variants

Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.     

Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics

Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.     

Visual coverage and scanning behavior in two corvid species: American crow and Western scrub jay

Inter-specific differences in the configuration of avian visual fields and degree of eye/head movements have been associated with foraging and anti-predator behaviors. Our goal was to study visual fields, eye movements, and head movements in two species of corvids: American crow (Corvus brachyrhynchos) and Western scrub jay (Aphelocoma californica). American crows had wider binocular overlap, longer vertical binocular fields, narrower blind areas, and higher amplitude of eye movement than Western scrub jays. American crows can converge their eyes and see their own bill tip, which may facilitate using different foraging techniques (e.g., pecking, probing) and manufacturing and handing rudimentary tools. Western scrub jays had a higher head movement rate than American crows while on the ground, and the opposite between-species difference was found when individuals were perching. Faster head movements may enhance the ability to scan the environment, which may be related to a higher perceived risk of predation of Western scrub jays when on the ground, and American crows when perching. The visual field configuration of these species appears influenced mostly by foraging techniques while their scaning behavior, by predation risk.     

Atypical squamous cells of undetermined significance in women over 55. Comparison with the general population and implications for management.

OBJECTIVE: To determine the significance of atypical squamous cells of undetermined significance (ASCUS) in patients 55 years or older. STUDY DESIGN: From January 1994, to January 1997, 8,175 cervicovaginal smears were obtained from patients 55 years or older (mean age, 64.8; range, 56-84) at University Hospitals of Cleveland. Ninety-six of these patients were diagnosed with ASCUS only or ASCUS with a qualifying statement on the smear. Patient records, follow-up cervicovaginal smears and biopsies were reviewed for a period of one to four years following the diagnosis of ASCUS. RESULTS: The incidence of ASCUS only or ASCUS with a qualifying statement for patients 55 years or older was 1.8%. The ASCUS:SIL ratio was 2.6:1. An estrogen stimulation test was recommended in two cases. Women older than 55 with ASCUS were three times more likely to be receiving hormonal replacement therapy than similar-aged women with normal cervicovaginal smears. Follow-up cervicovaginal smears or biopsies were obtained on 93 (80 cervicovaginal smears, 13 biopsies). The results were the following: LSIL (13), squamous carcinoma in situ (1) and ASCUS (53); the remainder of the cases were normal. In the patients who received a second diagnosis of ASCUS, follow-up cervi covaginal smears or biopsies revealed low grade dysplasia in six. CONCLUSION: Although the incidence of ASCUS and the frequency of underlying dysplasia is lower in postmenopausal women than the general population, there is still a real risk that a postmenopausal woman with ASCUS has underlying intraepithelial neoplasia. Therefore, these patients should be managed as is the general population.     

Extracellular electrical signals in a neuron-surface junction: model of heterogeneous membrane conductivity

Signals recorded from neurons with extracellular planar sensors have a wide range of waveforms and amplitudes. This variety is a result of different physical conditions affecting the ion currents through a cellular membrane. The transmembrane currents are often considered by macroscopic membrane models as essentially a homogeneous process. However, this assumption is doubtful, since ions move through ion channels, which are scattered within the membrane. Accounting for this fact, the present work proposes a theoretical model of heterogeneous membrane conductivity. The model is based on the hypothesis that both potential and charge are distributed homogeneously on the membrane surface, concentrated near channel pores, as the direct consequence of the inhomogeneous transmembrane current. A system of continuity equations having non-stationary and quasi-stationary forms expresses this fact mathematically. The present work performs mathematical analysis of the proposed equations, following by the synthesis of the equivalent electric element of a heterogeneous membrane current. This element is further used to construct a model of the cell-surface electric junction in a form of the equivalent electrical circuit. After that a study of how the heterogeneous membrane conductivity affects parameters of the extracellular electrical signal is performed. As the result it was found that variation of the passive characteristics of the cell-surface junction like conductivity of the cleft and the cleft height could lead to different shapes of the extracellular signals.     

Hawk Eyes I: Diurnal Raptors Differ in Visual Fields and Degree of Eye Movement

Background

Different strategies to search and detect prey may place specific demands on sensory modalities. We studied visual field configuration, degree of eye movement, and orbit orientation in three diurnal raptors belonging to the Accipitridae and Falconidae families.

Methodology/Principal Findings

We used an ophthalmoscopic reflex technique and an integrated 3D digitizer system. We found inter-specific variation in visual field configuration and degree of eye movement, but not in orbit orientation. Red-tailed Hawks have relatively small binocular areas (∼33°) and wide blind areas (∼82°), but intermediate degree of eye movement (∼5°), which underscores the importance of lateral vision rather than binocular vision to scan for distant prey in open areas. Cooper''s Hawks'' have relatively wide binocular fields (∼36°), small blind areas (∼60°), and high degree of eye movement (∼8°), which may increase visual coverage and enhance prey detection in closed habitats. Additionally, we found that Cooper''s Hawks can visually inspect the items held in the tip of the bill, which may facilitate food handling. American Kestrels have intermediate-sized binocular and lateral areas that may be used in prey detection at different distances through stereopsis and motion parallax; whereas the low degree eye movement (∼1°) may help stabilize the image when hovering above prey before an attack.

Conclusions

We conclude that: (a) there are between-species differences in visual field configuration in these diurnal raptors; (b) these differences are consistent with prey searching strategies and degree of visual obstruction in the environment (e.g., open and closed habitats); (c) variations in the degree of eye movement between species appear associated with foraging strategies; and (d) the size of the binocular and blind areas in hawks can vary substantially due to eye movements. Inter-specific variation in visual fields and eye movements can influence behavioral strategies to visually search for and track prey while perching.     

Purification and some catalytic properties of phosphoglucomutase from maize leaves

Phosphoglucomutase (EC 2.7.5.1, PGM) was purified to homogeneity from maize (Zea mays L.) leaves. The enzyme had specific activity 11. 7 U/mg protein and molecular mass (determined by gel-chromatography) of 133 +/- 4 kD. The molecular mass of PGM subunits determined by SDS-electrophoresis was 66 +/- 3 kD. The enzyme had Km for glucose-1-phosphate and glucose-1,6-diphosphate of 20.0 +/- 0.9 and 16.0 +/- 0.8 &mgr;M, respectively. Concentrations of glucose-1-phosphate and glucose-1,6-diphosphate above 3 and 0.4 mM, respectively, cause substrate inhibition. The enzyme activity was maximal at pH 8.0 and temperature 35 degreesC. Magnesium ions activate the enzyme and manganese ions inhibit it. 3-Phosphoglycerate is an uncompetitive inhibitor of the enzyme (Ki = 1.22 +/- 0.05 mM). Fructose-6-phosphate, 6-phosphogluconate, and ADP activate PGM, whereas ATP, UTP, and AMP inhibit the enzyme. Citrate was also a potent inhibitor, inhibitory effects of isocitrate and cis-aconitate being less pronounced.