Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue

The crystallographic structure of acetyl-Cys-Val-Ile-selenoMet-COOH and alpha-hydroxyfarnesylphosphonic acid (alphaHFP) complexed with rat farnesyl protein transferase (FPT) (space group P61, a = b = 174. 13 A, c = 69.71 A, alpha = beta = 90 degrees, gamma = 120 degrees, Rfactor = 21.8%, Rfree = 29.2%, 2.5 A resolution) is reported. In the ternary complex, the bound substrates are within van der Waals contact of each other and the FPT enzyme. alphaHFP binds in an extended conformation in the active-site cavity where positively charged side chains and solvent molecules interact with the phosphate moiety and aromatic side chains pack adjacent to the isoprenoid chain. The backbone of the bound CaaX peptide adopts an extended conformation, and the side chains interact with both FPT and alphaHFP. The cysteine sulfur of the bound peptide coordinates the active-site zinc. Overall, peptide binding and recognition appear to be dominated by side-chain interactions. Comparison of the structures of the ternary complex and unliganded FPT [Park, H., Boduluri, S., Moomaw, J., Casey, P., and Beese, L. (1997) Science 275, 1800-1804] shows that major rearrangements of several active site side chains occur upon substrate binding.     

Rhesus incompatibility and anti-D prevention in the Düsseldorf region (a ten-year survey) (author's transl)

Among 116 120 children born between 1964 and 1973, 512 (0.44%) required treatment for haemolytic disease of the newborn caused by the presence of irregular antibodies. While the incidence between 1964 to 1970 ranged between 0.42 to 0.56%, it fell from 1971 to 1973 to 0.28%, evidence for effective anti-D prophylaxis since 1971. Those cases still occurring after 1971 were largely due to pregnancies which had started before 1971. In addition there were abortions, sensitizations during the first pregnancy, but also blood transfusions as cause for new sensitizations. Sensitization after pregnancy despite anti-D prophylaxis was observed twice. In the last few years there has been a relative increase of rare antibodies, increasing the complexities of serological diagnosis. Safety and speed of treatment can be further improved by more frequent identification of irregular antibodies in the mother and regular reports to the paediatrician.     

Body size estimation in anorexia nervosa patients: the significance of overestimation

Using the video distortion method on a life-size screen, we have studied body size estimation in 100 female restricting anorexia nervosa patients. About half of the patients were accurate in estimating their own body dimensions and only 20% clearly showed overestimation. We then tested whether differences in accuracy of estimation were related to scores on the following questionnaires: Eating Disorder Inventory; Body Attitude Test; and Symptom Checklist (SCL-90). Overestimators reported a more negative body attitude and a more "neurotic profile" on the SCL-90. These differences might have both prognostic and therapeutic implications.     

Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism

Serotonergic 5-hydroxytryptamine-1A (5-HT1A) receptors are of interest in the pathophysiology of several neuropsychiatric disorders such as anxiety, depression and schizophrenia. [Carbonyl-11C]WAY-100635 has recently been shown to be suitable for quantitative determination of 5-HT1A receptors in the human brain using PET. For group comparisons of neuroreceptor distribution on a pixel-by-pixel basis, an anatomic standardization technique is required. In the current study, we have built a database of normal 5-HT1A receptor distribution using [carbonyl-11C]WAY-100635 and an anatomic standardization technique. METHOD: A PET examination lasting 63 min was performed on six subjects after intravenous injection of [carbonyl-11C]WAY-100635. The radioactivity of the PET images were integrated in the interval 12-63 min and normalized by the radioactivity of the cerebellum, providing a measure of the binding potential (BP) in each pixel. Each PET image was transformed into a standard brain anatomy using a computerized brain atlas system. From the standardized PET images, the sample mean and the SD of the BP were calculated in each pixel. RESULT: On the anatomically standardized average image, high BP was observed in the cerebral cortices, hippocampus and raphe nucleus, whereas low BP was observed in the basal ganglia and thalamus. This regional distribution is in good agreement with the distribution of 5-HT1A receptors known from in vitro studies. CONCLUSION: The anatomic standardization technique permits building of a database of the normal 5-HT1A receptor distribution in the living human brain. This technique can be applied for group comparisons of neuroreceptor distribution on a pixel-by-pixel basis.     

The placental transfer of sufentanil: effects of fetal pH, protein binding, and sufentanil concentration

This study investigated factors that influence the placental transfer of sufentanil using the dual-perfused, single-cotyledon human placental model. Placentas were collected from healthy women. Experiments were designed to elucidate the effects of maternal protein binding, changing maternal sufentanil concentration (1, 10, 20, and 100 ng/mL) and decreasing fetal pH (fetal acidemia 7.2, 7.0, 6.8) on the placental transfer of sufentanil. Sufentanil crossed the placenta rapidly at a rate two-thirds that of the transfer marker, antipyrine. Sufentanil transfer increased linearly with the maternal concentration (r = 0.999). Sufentanil/antipyrine maternal to fetal (M-->F) transfer ratios were significantly reduced (0.66 +/- 0.05 vs 0.40 +/- 0.04, P < 0.05) when fresh frozen plasma was added to the maternal circuit to enhance protein binding. Fetal pH and sufentanil transfer were related because sufentanil M-->F clearance increased significantly as the fetal pH decreased (r = 0.973, P < 0.05). Sufentanil appears to cross the placenta by passive diffusion but is modulated by the degree of maternal protein binding. Sufentanil M-->F transfer is enhanced by fetal acidemia.     

Distortions in infant electrocardiograms caused by inadequate high-frequency response

Frank lead ECG's from infants were studied for frequency content by introducing low-pass filters of 50, 75, 100, and 150 150 Hz bandwidths before obtaining computer measurements. Results indicated that a minimum bandwidth of 100 Hz is required to avoid amplitude error of 10 per cent or greater. This bandwidth requierement is essentially the same as that required for adult ECG's despite the fact that infant QRS durations are usually about half those of adults. Although the average infant ECG spectrum is likely to contain higher frequencies than the average adult ECG spectrum, duration values for Q, R, and S waves overlap in these populations to such an extent that bandwidth requirements are practically identical.     

Eigenvectors of directed graphs and importance scores: dominance,T-Rank,and sink remedies

We study the properties of the principal eigenvector for the adjacency matrix (and related matrices) for a general directed graph. In particular—motivated by the use of the eigenvector for estimating the “importance” of the nodes in the graph—we focus on the distribution of positive weight in this eigenvector, and give a coherent picture which builds upon and unites earlier results. We also propose a simple method—“T-Rank”—for generating importance scores. T-Rank generates authority scores via a one-level, non-normalized matrix, and is thus distinct from known methods such as PageRank (normalized), HITS (two-level), and SALSA (two-level and normalized). We show, using our understanding of the principal eigenvector, that T-Rank has a much less severe “sink problem” than does PageRank. Also, we offer numerical results which quantify the “tightly-knit community” or TKC effect. We find that T-Rank has a stronger TKC effect than PageRank, and we offer a novel interpolation method which allows for continuous tuning of the strength of this TKC effect. Finally, we propose two new “sink remedies”, i.e., methods for ensuring that the principal eigenvector is positive everywhere. One of our sink remedies (source pumping) is unique among sink remedies, in that it gives a positive eigenvector without rendering the graph strongly connected. We offer a preliminary evaluation of the effects and possible applications of these new sink remedies.