Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase

A three-dimensional structure model of the dihydrofolate reductase (DHFR) domain of the bifunctional DHFR-thymidylate synthase of Plasmodium falciparum was used as a basis for computational screening of commercially available compounds for candidate inhibitors. Compounds which can stably dock to the model with strong ionic hydrogen bonds via protonation by an aspartic acid residue at the bottom of the active site were identified through docking simulation. Among compounds thus identified, 21 were assayed for inhibitory activity towards the recombinant DHFR domain. Two compounds, 2-amino-1,4-dihydro-4,4,7,8-tetramethyl-s-triazino(1,2-a)benzimida zole and Trp-P-2, inhibited the recombinant P. falciparum DHFR domain with Ki values of 0.54 and 8.7 microM, respectively. Kinetic analysis showed that these compounds competitively inhibited the enzyme with respect to the substrate dihydrofolate. These findings support the validity of both the modeled structure and the docking results. Furthermore, these compounds serve as leads for developing new DHFR inhibitors, since their skeletal structures are different from any of known DHFR inhibitors. This paper also reveals a new biological activity of Trp-P-2, a potent mutagen.     

Energy dissipation from particulate systems undergoing a single particle crushing event

The energy dissipation from particulate systems undergoing particle crushing is often assumed to scale solely with the increase in surface area, irrespective of the strain energy stored in the surrounding media. By analyzing idealized particulate systems undergoing a single particle crushing event, this assumption is questioned and proven invalid. Two analysis types are considered. One represents the particulate system as an idealized assembly and then represents particle contact forces as members belonging to a periodic lattice. The other treats the particulate system as an elastic continuum. Different sizes of two and three dimensional particulate systems are considered, as well as isotropic and anisotropic confining stress states. The overall dissipation is shown to depend strongly on the dimensionality of the system, the anisotropy of the confining stress state and the elastic properties of the system. The ratio between dissipation due to stored elastic energy redistribution from surrounding media and dissipation by fracture surface energy is calculated. The ratio is found to diminish with the increasing dimensionality of the system. It is also shown that this ratio is independent of the fracture surface energy of the material. The most relevant analysis of a three dimensional particulate system to accurately estimate this ratio seems to be a one dimensional analysis of the force chain containing the most heavily loaded particles.     

On convexity, normality, pre-consolidation pressure, and singularities in modelling of granular materials

The issues of convexity, normality, pre- consolidation pressure, and singularities of yield surfaces are discussed in the context of granular materials and soil mechanics. We approach those subjects from a rather unusual direction, by expressing yield surfaces in strain space. It is shown that the convexity assumption in strain space is justified when the elastic behaviour is linear, but not otherwise. As the effective bulk modulus of granular matter is generally pressure dependent, strain space yield surfaces are non-convex. However, strain space non-convexity does not necessarily violate the laws of thermodynamics, and by acknowledging that, arguments in favor of strain space elasto-plasticity could be made. We then define the pre-consolidation pressure directly using the total volumetric strain. The new definition offers to combine the advantages of the classical definition based on the void-ratio and a theoretically consistent definition using the plastic volumetric strain. It also allows removing singularities that may occur due to a zero denominator in the definition of the non- negative plasticity multiplier.     

CT of the medial umbilical folds

PURPOSE: The goal of our study was to investigate the appearance of the medial umbilical folds on CT. METHOD: We retrospectively reviewed the CT images of 30 consecutive patients with massive ascites. In addition, we inspected the inner pelvic wall in cadavers. RESULTS: The medial umbilical folds were well recognized on CT in 21 of 30 patients, bilaterally in 20 and unilaterally in 1. In four patients the folds were undetectable after the ascites resolved. The CT findings were supported by those studied in cadavers, in which the folds were recognized as a peritoneal reflection in 13 of 20. CONCLUSION: We concluded that medial umbilical folds could be commonly visualized on CT when ascites was present.     

Segmented areas of increased attenuation in the liver caused by right adrenal tumors: CT features

OBJECTIVE: Our goal was to describe attenuation differences bordered by a straight line in the right hepatic lobe on enhanced CT in patients with right adrenal tumors and to discuss the cause of this appearance. MATERIALS AND METHODS: Three patients showing attenuation differences bordered by a straight line were discovered in the CT files of 26 cases of right adrenal tumor over 3 cm in diameter. All CT scans were examined by incremental dynamic study. RESULTS: Two patients had large zone of hyperattenuation in the right lobe bordered with a straight line intersecting both anterior branches of the right portal vein and the inferior vena cava (IVC). A third patient and one of the two patients mentioned already had zones of relative hyper- and hypoattenuation in the medial portion of the posterior hepatic segment, respectively. All three patients had large right adrenal tumors, which severely compressed the right hepatic vein near its confluence with the IVC and/or the IVC in or below its intrahepatic portion. The distribution of attenuation differences was similar to the hyperattenuation at CT arteriography or perfusion defect at CT arterial portography under temporary balloon occlusion of the right hepatic vein and inferior right hepatic vein, respectively. CONCLUSION: Straight-bordered attenuation differences within the right hepatic lobe at dynamic CT can be caused by compression of the right hepatic vein by large right adrenal tumors.     

Efficient emulation of single-hop radio network with collision detection on multi-hop radio network with no collision detection

Summary This paper presents an efficient randomized emulation ofsingle-hop radio networkwith collision detection onmulti-hop radio networkwithout collision detection. Each step of the single-hop network is emulated by rounds of the multi-hop network and succeeds with probability 1–. (n is the number of processors,D the diameter and the maximum degree). It is shown how to emulate any polynomial algorithm such that the probability of failure remains . A consequence of the emulation is an efficient randomized algorithm for choosing a leader in a multi-hop network. Reuven Bar-Yehuda was born in Iran, on July 17th 1951. Received B.A., M.Sc., and D.Sc. in Computer Science from the Technion — Israel Institute of Technology, Haifa, Israel, in 1978, 1980, and 1983, respectively. He is currently a Senior Lecturer of Computer Science at the Technion. From 1984 to 1986, he was a visiting assistant professor in the Computer Science Dept. at the Duke Univesity His research interests include computational geometry, VLSI, graph algorithms and distributed algorithms. Oded Goldreich was born in Tel-Aviv, Israel, on February 4th 1957. Received B.A., M.Sc., and D.Sc. in Computer Science from the Technion — Israel Institute of Technology, Haifa, Israel, in 1980, 1982, and 1983, respectively. He is currently an Associate Professor of Computer Science at the Technion. From 1983 to 1986, he was a postdoctoral fellow at MIT's Laboratory for Computer Science. His research interests include cryptography and related areas, relation between randomness and algorithms, and distributed computation. Alon Itai was born in Scotland, on December 12th 1946. Received B.Sc. in Mathematics from the Hebrew University in Jerusalem in 1969. M.Sc., and Ph.D. in Computer Science from the Weizmann Institute of Science, Rehovot, Israel in 1971 and 1976. He is currently an Associate Professor of Computer Science at the Technion. His research interests include randomized and distributed algorithms, computational learning theory and performance evaluation.The second author was partially supported by grant No. 86-00301 from the United States—Israel Bi-national Science Foundation BSF), Jerusalem, Israel.     

CT and MRI in detection of intrahepatic portosystemic shunts in patients with liver cirrhosis

OBJECTIVE: Our goal was to determine the prevalence and anatomic location of intrahepatic portosystemic shunts (IPSs) in patients with hepatic cirrhosis as shown by CT and MRI. MATERIALS AND METHODS: We retrospectively reviewed CT and MR scans of 33 cirrhotic patients who had IPSs. In addition, two series of 100 consecutive CT or MR were reviewed to determine the prevalence of IPSs and the percentage of intrahepatic and extrahepatic paraumbilical veins. RESULTS: Intrahepatic portosystemic shunts were divided into three groups according to the intrahepatic course: paraumbilical shunt between the left portal vein and the paraumbilical vein anterior to the liver (n = 29); inferior vena caval shunt between the posterior branch of the right portal vein and the inferior vena cava (n = 2); and miscellaneous (n = 2). Shunts of the paraumbilical type ran through the medial (n = 23), lateral (n = 3), or both medial and lateral (n = 3) segments of the left lobe of the liver. Twenty-five patients had one shunt, and four had more than one. Six cases were also associated with extrahepatic paraumbilical veins. CONCLUSION: Intrahepatic portosystemic shunts, especially the paraumbilical type, were not infrequently visualized in patients with hepatic cirrhosis.     

Hybrid structures composed of photosynthetic system and metal nanoparticles: plasmon enhancement effect

The efficiency of chemical energy production of a photosynthetic system can be strongly enhanced in the presence of metal nanoparticles. Two competing effects contribute to the photosystem efficiency: plasmon enhancement of photon fields inside the light-absorbing chlorophyll molecules and energy transfer from chlorophylls to metal nanoparticles. The first effect can lead to strong enhancement of light absorption by the chlorophylls, whereas the second can somewhat reduce the quantum yield of the system. This paper describes one concrete example of hybrid photosystem that incorporates a photosynthetic reaction center bound to gold and silver nanocrystals. The calculated rate of production of excited electrons inside the reaction center is strongly increased due to plasmon resonance and fast electron-hole separation. In phototransport experiments with photosynthetic reaction centers, the plasma resonance can enhance the photocurrent response. The enhancement mechanism described here can be utilized in energy-conversion devices and sensors.