A sampling problem in molecular dynamics simulations of macromolecules.

Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled.

Potent inhibition of tumor survival in vivo by β-lapachone plus taxol: Combining drugs imposes different artificial checkpoints

Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of β-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after β-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. β-Lapachone causes cell-cycle delays in late G1 and S phase, and taxol arrests cells at G2/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone “collisions” at cell-cycle checkpoints.

Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons

The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first-generation vectors expressing hAAT. Transgene expression was limited to approximately 3–5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes.

Invariance between subjects of brain wave representations of language

In three experiments, electric brain waves of 19 subjects were recorded under several different experimental conditions for two purposes. One was to test how well we could recognize which sentence, from a set of 24 or 48 sentences, was being processed in the cortex. The other was to study the invariance of brain waves between subjects. As in our earlier work, the analysis consisted of averaging over trials to create prototypes and test samples, to both of which Fourier transforms were applied, followed by filtering and an inverse transformation to the time domain. A least-squares criterion of fit between prototypes and test samples was used for classification. In all three experiments, averaging over subjects improved the recognition rates. The most significant finding was the following. When brain waves were averaged separately for two nonoverlapping groups of subjects, one for prototypes and the other for test samples, we were able to recognize correctly 90% of the brain waves generated by 48 different sentences about European geography.

Invariance of brain-wave representations of simple visual images and their names

In two experiments, electric brain waves of 14 subjects were recorded under several different conditions to study the invariance of brain-wave representations of simple patches of colors and simple visual shapes and their names, the words blue, circle, etc. As in our earlier work, the analysis consisted of averaging over trials to create prototypes and test samples, to both of which Fourier transforms were applied, followed by filtering and an inverse transformation to the time domain. A least-squares criterion of fit between prototypes and test samples was used for classification. The most significant results were these. By averaging over different subjects, as well as trials, we created prototypes from brain waves evoked by simple visual images and test samples from brain waves evoked by auditory or visual words naming the visual images. We correctly recognized from 60% to 75% of the test-sample brain waves. The general conclusion is that simple shapes such as circles and single-color displays generate brain waves surprisingly similar to those generated by their verbal names. These results, taken together with extensive psychological studies of auditory and visual memory, strongly support the solution proposed for visual shapes, by Bishop Berkeley and David Hume in the 18th century, to the long-standing problem of how the mind represents simple abstract ideas.