A mutant yeast topoisomerase II (top2G437S) with differential sensitivity to anticancer drugs in the presence and absence of ATP

To further characterize the mechanistic basis for cellular resistance/hypersensitivity to anticancer drugs, a yeast genetic system was used to select a mutant type II topoisomerase that conferred cellular resistance to CP-115,953, amsacrine, etoposide, and ellipticine. The mutant enzyme contained a single point mutation that converted Gly437 --> Ser (top2G437S). Purified top2G437S displayed wild-type enzymatic activity in the absence of drugs but exhibited two properties that were not predicted by the cellular resistance phenotype. First, in the absence of ATP, it was hypersensitive to all of the drugs examined and hypersensitivity correlated with increased drug affinity. Second, in the presence of ATP, top2G437S lost its hypersensitivity and displayed wild-type drug sensitivity. Since the resistance of yeast harboring top2G437S could not be explained by alterations in enzyme-drug interactions, physiological levels of topoisomerase II were determined. The Gly437 --> Ser mutation reduced the stability of topoisomerase II and decreased the cellular concentration of the enzyme. These findings suggest that the physiological drug resistance phenotype conferred by top2G437S results primarily from its decreased stability. This study highlights the need to analyze both the biochemistry and the physiology of topoisomerase II mutants with altered drug sensitivity in order to define the mechanistic bridge that links enzyme function to cellular phenotype.     

Review of Schreber: Father and son.

Reviews the book, Schreber: Father and son by Han Isra?ls (see record 1989-98605-000). In 1911, Sigmund Freud published a long paper about a German judge, Daniel Paul Schreber (1842-1911), who had been an inpatient in three psychiatric clinics from 1893 to 1902. Beginning in the 1940s and 1950s, psychiatrists and psychoanalysts began to give intensive attention to the life and illness of Schreber, an interest that has continued to the present day. Now Han Isra?ls, has written a compelling and most unusual book about Schreber and his father, Moritz Schreber. From one point of view it is a historical tour de force, bound to evoke admiration from any professional historian for its research and scholarship. From another vantage point, it is an example of historical overkill. The dominant theme of Isra?ls's book is an exposé of the corrupt scholarship that has grown up around Moritz Schreber and hence Isra?ls's argument that after his death Moritz achieved fame and notoriety far out of proportion to his actual contributions. A second, minor theme is Isra?ls's agreement with the discovery made by the psychoanalyst Niederland that Moritz Schreber's writings provide information about the way he reared his children: "It has become apparent that the method of upbringing has left traces in the psychotic illness [of Paul Schreber]." When all is said and done, we are left with a book which, in spite of its compelling scholarship, yields almost no new information about Judge Schreber that would help us to understand him better. Furthermore, Isra?ls's book is likely to have little impact on the modern and incorrect views about Schreber's father. In the end, Isra?ls's book stands as a cautionary tale to lazy researchers and sloppy scholars. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nonlinear fuzzy rule-based approach for estimating video trafficrate

The authors investigate a fuzzy logic-based video rate control technique which aims to regulate compressed video to a constant transmission rate, without incurring objectionable quality degradation. Conventional fuzzy rule-based control (FRC) does not adequately control the output video quality. Video information is therefore added into the FRC design by incorporating feed-forward scaling factors, derived from scene change features. The performance of this coder has been compared with other approaches measuring buffer occupancy, the number of coded bits per frame and peak signal-to-noise ratio     

Predictors of fear of falling in dizzy and nondizzy elderly.

Fear of falling may constitute an independent risk factor for disability, leading older people to unnecessarily restrict their activity. Sixty older adults with chronic dizziness and 66 healthy controls were studied to help clarify the interrelationships among demographic factors, psychological status, physical health, and fear of falling. Chronic dizziness was strongly associated with fear of falling; among dizzy patients, nearly half (47%) expressed fear of falling, in comparison with 3% of controls. In participants with dizziness, 3 factors predicted fear of falling: an activity of daily living score, the revised Symptom Checklist 90 Depression (L. R. Derogatis, 1983) score, and stability when standing with feet together. These results support the concept that fear of falling is multiply determined and that psychological factors play a major role in influencing the symptoms and responses in many older patients with dizziness. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Small‐Molecule Proteomimetic Inhibitors of the HIF‐1α–p300 Protein–Protein Interaction

The therapeutically relevant hypoxia inducible factor HIF‐1α–p300 protein–protein interaction can be orthosterically inhibited with α‐helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C‐terminal helix of the HIF‐1α C‐TAD (C‐terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side‐chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF‐1α–p300 PPI inhibitors and the first examples of small‐molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF‐1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42‐residue HIF‐1α C‐TAD from which it is derived.     

Constitutive modelling of arteries considering fibre recruitment and three-dimensional fibre distribution

Structurally motivated material models may provide increased insights into the underlying mechanics and physics of arteries under physiological loading conditions. We propose a multiscale model for arterial tissue capturing three different scales (i) a single collagen fibre; (ii) bundle of collagen fibres; and (iii) collagen network within the tissue. The waviness of collagen fibres is introduced by a probability density function for the recruitment stretch at which the fibre starts to bear load. The three-dimensional distribution of the collagen fibres is described by an orientation distribution function using the bivariate von Mises distribution, and fitted to experimental data. The strain energy for the tissue is decomposed additively into a part related to the matrix material and a part for the collagen fibres. Volume fractions account for the matrix/fibre constituents. The proposed model only uses two parameters namely a shear modulus of the matrix material and a (stiffness) parameter related to a single collagen fibre. A fit of the multiscale model to representative experimental data obtained from the individual layers of a human thoracic aorta shows that the proposed model is able to adequately capture the nonlinear and anisotropic behaviour of the aortic layers.     

Coaxial ion trap mass spectrometer: concentric toroidal and quadrupolar trapping regions

We present the design and results for a new radio-frequency ion trap mass analyzer, the coaxial ion trap, in which both toroidal and quadrupolar trapping regions are created simultaneously. The device is composed of two parallel ceramic plates, the facing surfaces of which are lithographically patterned with concentric metal rings and covered with a thin film of germanium. Experiments demonstrate that ions can be trapped in either region, transferred from the toroidal to the quadrupolar region, and mass-selectively ejected from the quadrupolar region to a detector. Ions trapped in the toroidal region can be transferred to the quadrupole region using an applied ac signal in the radial direction, although it appears that the mechanism of this transfer does not involve resonance with the ion secular frequency, and the process is not mass selective. Ions in the quadrupole trapping region are mass analyzed using dipole resonant ejection. Multiple transfer steps and mass analysis scans are possible on a single population of ions, as from a single ionization/trapping event. The device demonstrates better mass resolving power than the radially ejecting halo ion trap and better sensitivity than the planar quadrupole ion trap.