Machine learning-, rule- and pharmacophore-based classification on the inhibition of P-glycoprotein and NorA.

The efflux pumps P-glycoprotein (P-gp) in humans and NorA in Staphylococcus aureus are of great interest for medicinal chemists because of their important roles in multidrug resistance (MDR). The high polyspecificity as well as the unavailability of high-resolution X-ray crystal structures of these transmembrane proteins lead us to combining ligand-based approaches, which in the case of this study were machine learning, perceptual mapping and pharmacophore modelling. For P-gp inhibitory activity, individual models were developed using different machine learning algorithms and subsequently combined into an ensemble model which showed a good discrimination between inhibitors and noninhibitors (acctrain-diverse = 84%; accinternal-test = 92% and accexternal-test = 100%). For ligand promiscuity between P-gp and NorA, perceptual maps and pharmacophore models were generated for the detection of rules and features. Based on these in silico tools, hit compounds for reversing MDR were discovered from the in-house and DrugBank databases through virtual screening in an attempt to restore drug sensitivity in cancer cells and bacteria.

Three- and four-class classification models for P-glycoprotein inhibitors using counter-propagation neural networks.

P-glycoprotein (P-gp) is an ATP binding cassette (ABC) transporter that helps to protect several certain human organs from xenobiotic exposure. This efflux pump is also responsible for multi-drug resistance (MDR), an issue of the chemotherapy approach in the fight against cancer. Therefore, the discovery of P-gp inhibitors is considered one of the most popular strategies to reverse MDR in tumour cells and to improve therapeutic efficacy of commonly used cytotoxic drugs. Until now, several generations of P-gp inhibitors have been developed but they have largely failed in preclinical and clinical studies due to lack of selectivity, poor solubility and severe pharmacokinetic interactions. In this study, three models (SION, SIO, SIN) to classify specific 'true' P-gp inhibitors as well as three other models (CPBN, CPB1, CPN) to distinguish between P-gp inhibitors, CYP 3A inhibitors and co-inhibitors of these proteins with rather high accuracy values for the test set and the external set were generated based on counter-propagation neural networks (CPG-NN). Such three and four-class classification models helped provide more information about the bioactivities of compounds not only on one target (P-gp), but also on a combination of multiple targets (P-gp, CYP 3A).

Performance of the Euroline Western blot assay in the detection of herpes simplex virus type 2 antibody in Uganda, China and the USA.

Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted infections (STIs) worldwide. While glycoprotein G-2 enzyme-linked immunosorbent assays are commonly used for the serological detection of HSV-2 antibodies, they have low specificity in developing countries. The Euroline Western blot (WB) is a commercially available assay that is easy to perform; however, little is known about its performance characteristics. This study evaluated Euroline WB for the detection of HSV-2 antibodies compared with University of Washington Western blot in three geographically different regions: Baltimore, MD, USA; Rakai, Uganda; and Kunming, China. Among the 135 American men attending a STI clinic in Baltimore, MD, 72% (n = 97) were HSV-2-positive by Euroline WB, showing a sensitivity of 97.8% and a specificity of 81.8%. Among the 273 commercial sex workers in Kunming, 62.3% were HSV-2-positive by Euroline WB (sensitivity 96.9%, specificity 89.1%). Among the 437 Ugandans in Rakai, 67.3% were HSV-2-positive by Euroline WB (sensitivity 98.7%, specificity 65.4%). The Euroline WB has a consistently high sensitivity, but specificity varied significantly among the different locations.

Herpes simplex virus type 2 infection among commercial sex workers in Kunming, Yunnan Province, China.

A cross-sectional survey was conducted to determine the sociodemographic correlates of herpes simplex virus type 2 (HSV-2) infection among male and female commercial sex workers in Kunming, Yunnan Province of China. HSV-2 prevalence was 33.0%, human immunodeficiency virus (HIV) infection was 2.4% and hepatitis C virus (HCV) infection was 6.8%. Subjects who were positive for HSV-2 had a significantly higher prevalence of HIV infection (5.5% versus 0.9%, P = 0.002; odds ratio [OR]: 6.4, P = 0.006) and HCV infection (18.7% versus 2.4%, P < 0.001; OR: 7.6, P < 0.001) compared with HSV-2-negative individuals. Risk factors that increased the odds of HSV-2 infection were HIV infection, HCV infection, being female, and having a steady sex partner within the last six months (P < or = 0.01). In a multivariate analysis, being female (OR: 6.6, P < 0.001), having HCV infection (OR: 5.9, P < 0.001) and having a sex partner within the last six months (OR: 2.2, P < 0.05) showed greater odds of being infected with HSV-2. A strong relationship was found between HSV-2, HIV and HCV infections.

Distribution of blood flow between embryo and vitelline bed in the stage 18, 21 and 24 chick embryo.

OBJECTIVE: We defined the distribution of blood flow between the embryo and the extraembryonic vascular bed as an initial step in understanding the control of flow distribution in the early developing heart. METHODS: Dorsal aortic blood flow of stage 18, 21, and 24 chick embryo (n > or = 7 at each stage) was measured with a 20 MHz pulsed-Doppler velocity meter. Analog waveforms were digitally sampled at 500 Hz. 1-5 x 10(3) yellow microspheres in saline suspension were injected into the vitelline vein. The embryo and the extraembryonic vascular bed were harvested and separated from each other. The dye on the microspheres from each portion was extracted and extrapolated from the standard curve of the absorbance of dye concentrations per number of microspheres quantified by spectrophotometry. Blood flow was calculated from the integral of blood velocity and aortic cross-sectional area multiplied by the fraction distribution of microspheres in the embryo and extraembryonic vascular bed. Data were presented as mean +/- standard error of the mean. RESULTS: The proportion distribution of microspheres between embryo and extraembryonic vascular bed shifted from 18.7 +/- 2.5 vs. 81.3 +/- 2.5% at stage 18, 25.1 +/- 3.0 vs. 74.9 +/- 3.0% at stage 21, and 34.2 +/- 2.4 vs. 65.8 +/- 2.4% at stage 24. Indices of blood flow normalized to wet weight (mean +/- 95% confidence interval) were similar between the embryo and the extraembryonic vascular bed, but increased throughout the stages. CONCLUSION: During embryogenesis, blood flow per unit mass is evenly distributed between the metabolically active embryo and the extraembryonic vascular bed.

Incidence of aneurysm formation after Dacron patch aortoplasty repair for coarctation of the aorta: long-term results and assessment utilizing magnetic resonance angiography with three-dimensional surface rendering.

OBJECTIVES: Magnetic resonance angiography with three-dimensional surface rendering was performed to determine its value in assessing anatomic detail in patients with suspected aortic aneurysms. BACKGROUND: Dacron patch aortoplasty repair of coarctation of the aorta carries an inherent risk of aneurysm development. Sudden death from aortic rupture prompted discontinuing this operation and evaluating 39 patients (16 girls; mean age 6.3 years, range 10 days to 14.5 years) undergoing repair between January 1976 and October 1987. The aorta ruptured in 10 patients; 6 died at a mean interval of 8.1 years (range 0.75 to 12.4) after repair. All 33 survivors were interviewed and examined. METHODS: Conventional magnetic resonance imaging was performed in 26 patients, magnetic resonance angiography in 18. Angiographic slices were used to reconstruct three-dimensional images. No catheterization or contrast angiography was performed. Surgical intervention was based on clinical findings and magnetic resonance images. RESULTS: Twenty patients (11 girls) developed aneurysms, of which nine were detected in patients studied by magnetic resonance. Ruptures occurred in eight female patients, three of whom were pregnant. Surface renderings accurately defined aortic anatomy or aneurysms in all patients. On follow-up, no aneurysms have been detected in patients with negative magnetic resonance study results. Precise anatomic correlation with operative findings was reported. CONCLUSIONS: Magnetic resonance angiography with three-dimensional surface rendering provides noninvasive, radiation-free and contrast agent-free high resolution images of the thoracic aorta. These images can be reviewed and have three-dimensional form and perspective. These techniques were preferred over invasive angiography by surgeons and clinicians as definitive, risk-free procedures before surgical intervention.

A Phaseolus lectin anterograde tracing study of the tectorotundal projections in the domestic chick.

The projection from the chick optic tectum to the nucleus rotundus was investigated by iontophoresis of the anterograde tracer Phaseolus vulgaris lectin (PHA-L) into the optic tectum and by Golgi impregnation. PHA-L labelled fibres were observed within the ipsilateral nucleus rotundus and to course through the supraoptic decussation to the contralateral nucleus rotundus. They appeared similar to fibres evident in Golgi impregnated material. Before reaching the nucleus rotundus, PHA-L labelled fibres gave off short terminal branches in the caudoventral thalamic nucleus. Within the ipsilateral nucleus rotundus, the labelled fibres formed an extensive fibre net with a dense core and a less dense periphery. PHA-L labelled fibres in the contralateral nucleus rotundus exhibited a qualitatively similar but sparser distribution. There appeared to be a topographic representation of the optic tectum within the nucleus rotundus. Electron microscopy revealed that PHA-L labelled tectal fibres established asymmetric synapses with principal neurons in the nucleus rotundus.

Some data on GABA-ergic innervation of nucleus rotundus in chicks.

The EM preparates displayed in the nucleus rotundus also symmetrical type of synapses with flattened vesicles, known this type as inhibitory synapsis. To prove this supposition and to find the sources of inhibitory terminals GABA-immunostaining was applied in the diencephalon of chicks. The preparates were examined by light- and electronmicroscope. In nucl. rotundus the large terminal profiles on the cell membrane of principal neurons, on the dendrites and branching areas of terminal branchings of dendrites proved to be GABA positive. The sources of GABA-ergic fibers seemed to be the subpretectal and ventral posterior thalamic nuclei.

EM and EM Golgi study on structure of nucleus rotundus in chicks.

The analysis of EM structure of nucleus rotundus completes the results got by Golgi study. The fine structure of neurons and neuropil of the nucleus and the synaptic relations were studied by EM. The fine structural details of principal neuron were described. Several synapses of symmetrical type with flattened vesicles in large terminals contacted the cell body and also the origin and proximal part of the main dendrites. In the neuropil synaptic junctions were formed by terminals that contained (1) spherical vesicles with occasionally very few dense core vesicles, (2) flattened synaptic vesicles. Terminals that contained spherical vesicles were associated with asymmetric synaptic densities, and terminals that contained flattened vesicles formed symmetric junctions. Synapses of asymmetric type associated mostly with terminal sections of dendrites forming glomerular-like structure. Synapses of symmetric type with flattened synaptic vesicles contacted the branching areas of dendritic terminals and side-branches, the origin of main dendrites and the cell surface of principal neuron.