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Biomedical subjects

L E Lipkin

Publications and source records attributed to L E Lipkin.

At least 19 recordsLinked to original sources
PubMed1987

An interactive dot matrix system for locating potentially significant features in nucleic acid molecules.

An interactive computer system using a dot matrix approach has been developed and used to determine potentially significant features due to distortions in the B-DNA helix as a result of variations of purine and pyrimidine patterns. Sequences were compared using matrices which were generated using the Calladine-Dickerson rules (C.R. Calladine, J. Mol. Biol. 161, 343-352, 1982 and R.E. Dickerson, J. Mol. Biol. 166, 419-441, 1983). Having control over various parameters to enhance different aspects of the visual appearance of these matrices was helpful in discovering patterns that were not known a priori. Specifically, it was found that a pattern of alternating doublets of purines and pyrimidines appear to exist in regulatory regions. This event is shown to be beyond probabilistic expectation.

Base Sequence↗
PubMed1986

A sequence analysis system encompassing rules for DNA helical distortion.

Recently, it has been shown by Calladine (1982) and Dickerson (1983) that DNA distortions due to steric clashes between opposing purines and pyrimidines can be quantitated based upon four sum functions. The distortions involve helical twist, roll, torsion angle variations and propeller twist. It is the contention of the authors that these perturbations in structure act as information carriers for various external DNA interactions. This paper describes a system that incorporates these four rules and various other functions that permit the systematic interactive exploration for significant patterns as a consequence of these steric clashes.

Base Sequence↗
PubMed1986

Coordinate regulation of the expression of axonal proteins by the axonal microenvironment.

The axonal functions that act in the formation of the neuronal network have been shown to occur in close interdependence with the tissue that surrounds the growing axons. However, little is known about the molecular building blocks underlying axonal functions, although more than 400 axonal proteins have been identified. In view of the existence of such a large number of axonal proteins, we have initiated a project to determine the molecules involved in the implementation of particular axonal functions by a selective approach. On the assumption that plasticity in the expression of axonal functions in response to specific features of the local axonal environment may be based on changes in the expression of particular axonal proteins, the axonal proteins of dorsal root ganglion (DRG) neurons were screened for those whose expression responds to environmental influences. DRG neurons were grown in a compartmental cell system that offers separate access to neuronal somas and to their axons and the axons were locally exposed to different populations of cells from the peripheral or central nervous system. The axonal proteins were metabolically labeled and subjected to two-dimensional gel electrophoresis. Computerized quantitation of the individual axonal proteins revealed that the cocultured cells modulate the synthesis of a few axonal proteins of DRG neurons differentially. The data on the abundance of the newly expressed proteins under varying local environmental conditions were condensed as expression profiles. Comparison of expression profiles and cluster analysis of quantitative gel analysis data revealed that the environmentally modulated proteins subdivide into clusters with common distinct expression profiles under the influence of nonneuronal cells from the peripheral nervous system, nonneuronal cells of the central nervous system, and spinal cord cells, which are composed of neurons and nonneuronal cells. By means of this new, characteristic attribute assigned to environmentally modulated axonal proteins, working hypotheses were made as to their functional role.

Animals↗
PubMed1985

Differential modulation of the expression of axonal proteins by non-neuronal cells of the peripheral and central nervous system.

Axonal behavior during the formation of the neuronal network of the nervous system has been shown to be under environmental control. Hence, as a first step in a project aiming to elucidate the molecular basis of axonal functions, we have identified axonal proteins whose synthesis is subject to environmentally induced changes. Neurons from chicken embryonic dorsal root ganglia (DRG) were grown in a compartmental cell culture system that allows selective examination of axonal proteins. Non-neuronal cells of the peripheral or central nervous system were co-cultured with the DRG axons. The axonal proteins expressed under these different environmental conditions were examined by metabolic labeling and two-dimensional SDS-polyacrylamide gel electrophoresis. Computerized quantification revealed that 12 out of 400 axonal proteins responded to changes in the local axonal environment by a change in their relative abundance. Some proteins changed in response to both types of co-cultures whereas some changed specifically under the influence of either peripheral or central non-neuronal cells.

Animals↗
PubMed1984

Enhancer elements share local homologous twist-angle variations with a helical periodicity.

Several experiments have shown that some enhancers can be exchanged between different genomes. The transferred enhancers were functional (cf. Levinson, B., Khoury, G., Vande Woude, G. and Gruss, P. (1982) Nature 295, 568-572). This argues that these exchanged fragments are recognized as enhancers and possess some common characteristics which other sequences lack. Extensive comparisons of enhancers yielded only very limited nucleotide sequence homology, which appears to be insufficient for enhancer recognition. We suggest that the enhancers located and sequenced to date have recurring, periodic homologous twist-angle (tg) patterns. This helical periodicity and the symmetric nature of the repeating twist-angle features present a recurring spatial geometry. It also offers a possible explanation of the fact that inverted enhancers are still functional. Regions of large twist, roll or main-chain torsion angle delta deviations from regular B-DNA may facilitate enhancer recognition especially when distant from promoter elements. Tissue specificity may be encoded in additional sequence or structural features.

Animals↗
PubMed1984

DNAase I hypersensitive sites may be correlated with genomic regions of large structural variation.

Helical-twist, roll and torsion-angle variations calculated by the Calladine (1982)-Dickerson (1983) rules were scanned along several nucleotide sequences for which DNAase I cleavage data are available. It has been shown that for short synthetic oligomers DNAase I cuts preferentially at positions of high helical twist (Dickerson & Drew, 1981; Lomonossoff et al., 1981). Our calculations indicate that DNAase I sensitive and hypersensitive sites in chromatin are correlated with regions of successive, large, helical-twist angle variations from regular B-DNA. In many cases these regions exhibit large variations in base-pair roll and backbone torsion angles as well. It has been suggested that DNAase I cuts in the vicinity of cruciforms. However, it was recently demonstrated by Courey & Wang (1983) and Gellert et al. (1983) that such cruciform formation in a negatively supercoiled DNA is kinetically forbidden under physiological conditions. We thus propose that clustering of large twist-angle (and/or roll and backbone torsion angle) variations may be among the conformational features recognized by the enzyme. Specific cuts can then preferentially occur at base-pair steps with high helical twists.

Animals↗
PubMed1984

Generating non-overlapping displays of nucleic acid secondary structure.

A new algorithm is presented which permits the display of nucleic acid secondary structure by computer. This algorithm circumvents the problem of overlapping portions of the molecule which is inherent in some other drawing programs. The results from this algorithm may also be used as input to the drawing algorithm previously reported in this journal [1] to untangle most of a drawing. The algorithm also represents the molecule in a form which makes visual comparisons for similarity quite easy since it guarantees that comparable features will reside in the same relative position in the drawings when the drawings are normalized.

Base Sequence↗
PubMed1984

Identification of coordinate pairs of polypeptides: a technique for screening of putative precursor product pairs in 2D gels.

Two-dimensional electrophoresis, combined with computerized quantification of individual proteins, provides a sensitive and accurate approach to detection of small differences in the protein pattern. As an extension of "GELLAB," a data base system for the analysis of two-dimensional electrophoretic gels, we report here on a screening algorithm for detection of certain post-translational modification events. It is based on the assumption that, if there is a post-translational modification of a protein in the transition between two functional states of a biological system, in many cases the sum of the protein concentration of a precursor-product pair in one is equivalent to that in the other. In addition to the identification of candidate pairs with a precursor-product relationship, cues to the nature of the post-translational modification that might relate them might also be derived from comparisons of the isoelectric point and apparent molecular mass. This subset of the GELLAB system may be thought of as a screening tool in the search for and investigation of post-translational protein-processing events so that the more time-consuming structural investigations to follow can be performed on a smaller set of proteins.

Animals↗
PubMed1982

An interactive technique for the display of nucleic acid secondary structure.

The ability to visualize nucleic acid secondary structure has become quite important since the advent of computer prediction and biochemical techniques that depict such structures. Manually drawing the conformations can be quite time consuming and tedious. Thus, the ability to draw with the aid of a computer the secondary structure of nucleic acid molecules is quite advantageous. This paper describes an interactive algorithm that permits one to generate such drawings which may then be used for further analysis and/or publications.

Animals↗
PubMed1982

Some extensions to the GELLAB two-dimensional electrophoretic gel analysis system.

Several important extensions to the GELLAB 2D electrophoresis gel analysis system are discussed, including concepts that lead to the generation of consistent gel maps for a particular cell line, as illustrated by some recent results for the P388D1 cell system, GELLAB is an interactive graphics computer system that facilitates (a) image accessioning, (b) spot-data extraction from the image with position and density quantitation, (c) pairing of corresponding spots between gels, and (d) spot analysis for a large number of corresponding spots (over 3000 per gel) for up to 128 gels. Multiple gels are accessioned into the system used to create a composite gel data base. These then may be partitioned into multiple classes of gels and searched for statistically significant interclass spot differences, which can be visualized in reference map images of selected spot sets as well as mosaic images of particular spots in all gels. In addition to the visual feedback that is available during the gel analysis, various statistical, numerical, and other displays may be generated in the CGELP interactive program of the GELLAB system.

Animals↗
PubMed1980

Cellular effects of asbestos and other fibers: correlations with in vivo induction of pleural sarcoma.

The phenomenon of fiber-induced cytotoxicity to P388D1 macrophagelike cells has been demonstrated to parallel (thus far without exception) the probability that the fiber will induce a pleural sarcoma (mesothelioma) in rats. This startling parallel in both cases seems to be essentially independent of the chemical nature of the fiber and correlates best with the presence of fibers greater than 8 micrometers in length and fibers with diameters in the range 0.5 to 1.0 micrometer (Stanton Hypothesis). In both systems evidence has been produced which cast strong doubts on any role played by absorbed (or adherent) impurities. The existence of multiple physical forms of the same chemical moiety (aluminum oxide, dihydroxy-sodium aluminum carbonate, borosilicate glass, etc.,) provides additional test material for the chemical independence corollary. The similar, cytotoxic or sarcomatogenous behavior of chemically different materials (e.g. amosite, chrysotile, aluminum oxide) exhibits the necessary converse argument. As long as the fiber size-shape dependency effect was limited to whole animal phenomena, such as tumor induction, one could make implicitly what were essentially statistical or probabilistic inferences involving transport and/or distribution of fibers to account for the physical effect. The demonstration of strict parallelism at the cellular level in vitro suggests the possibility that in the case of durable fiber toxicology we are dealing with a form of cell-solid interaction in which physical properties for which we have as yet no known receptors play a prominent role.

Aluminum↗
PubMed1980

Data-base techniques for multiple two-dimensional polyacrylamide gel electrophoresis analyses.

Two-dimensional protein electrophoresis can benefit from a powerful set of computer-supported image processing and data structure/management procedures. Detection of quantitative differences is complicated by local inhomogeneities in the polyacrylamide base; biochemical changes and variations in temperature and preparative technique also make the between-gel density and x-y coordinate correspondences quite imprecise. The program presented here provides local alignment and computer-controlled variable "flicker" rates for multiple gels, with use of an interactive display system. Manual spot densitometry, referred to a National Bureau of Standards density wedge, can be complemented by a set of automatic densitometry routines for previously established lists of spots. The ability to establish a set of local landmarks, either by included standards or user identification, provides a basis for automatic n-way gel comparison for subsets or for the entire set of spots. Automatic segmentatin algorithms allow isolatin of spots and separation of touching and partially overlapping regions. Various analytical and statistical facilities are part of the user's access to the interactively developed data base. The data-structure and image-manipulation techniques developed here allow for user-directed and heuristic comparisons with online presentation of intermediate and final results.

Asbestosis↗
PubMed1978

Device for quantitative cytochemistry: a computerized scanning microdensitometer 'grain counter'.

A computerized scanning microdensitometer and autoradiographic grain counter was able to provide quantitative data on the cytochemical final reaction product formed within a single cell and also quantitate the kinetics of its formation. Optical density and area measurements were performed on hundreds of leukocytes from slides previously stained to demonstrate any one of a variety of reactions. These included cellular glycogen, lipids, peroxidase, esterases, alkaline phosphatase, and acid phosphatase. In addition to these slide studies, chamber studies with an adapted Dvorak-Stotler Chamber allowed the measurement of enzyme kinetics within single cells.

Autoradiography↗