I.E. Tamm is one of the great figures of 20th century physics and the mentor of the late A.D. Sakharov. Together with I.M. Frank, he received the Nobel Prize in 1958 for the explanation of the Cherenkov effect. This book contains a commented selection of his most important contributions to the physical literature and essays on his contemporaries - Mandelstam, Einstein, Landau, and Bohr - as well as his contributions to Pugwash conferences. About a third of the selections originally appeared in Russian and are, to our knowledge, for the first time now available to Western readers. This volume includes a preface by Sir Rudolf Peierls, a biography compiled by Tamm's former students, V.Ya. Frenkel and B.M. Bolotovskii, and a complete bibliography.

Serum withdrawal from either growing or quiescent Balb/c-3T3 murine fibroblasts causes a loss of F-actin fibres and focal adhesions within 30 min. Cells that are growing survive serum deprivation, whereas the great majority of density-arrested quiescent cells die during a period of up to 5 h from serum withdrawal. During this time an approximately constant fraction of the quiescent cell population dies per unit time. The population half-life is 60–70 min during this time. Addition of an appropriate cell growth factor or second messenger agonist at the time of serum withdrawal or within 2 h after serum withdawal protects a similar fraction of viable cells. These findings suggest a model according to which withdrawal of serum (i.e. growth factors) initiates the death process in cells of the population with kinetics that approximate first-order kinetics. We postulate that appropriate growth factors or second messenger agonists block the initiating event that starts the cell death process.

The great majority of murine Balb/c-3T3 fibroblasts in density-inhibited, quiescent cultures disintegrate and die rapidly when cells are deprived of serum in the medium. Platelet-derived growth factor (PDGF, 5 ng/ml) used alone and insulin-like growth factor (IGF-1, 40 ng/ml) + epidermal growth factor (EGF, 10 ng/ml) prevent most of this cell death and all three factors used together protect close to all cells in the confluent monolayer as determined by counting trypsinized cell suspensions in a Coulter counter. IGF-1 used alone affords a high level of protection during the first 5 hours of incubation in serum-free medium but the protective effect declines subsequently unless EGF is also present. EGF alone has little protective activity. The survival-promoting activity of PDGF used alone or of PDGF + EGF + IGF-1 is not significantly decreased by selective inhibition of messenger precursor RNA transcription with 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB, 20 or 40 microM), which prevents G1 traverse of the cells mediated by the combination of the three growth factors. DRB also does not interfere with the early protective effect of IGF-1 + EGF, but decreases the late protective effect of this growth factor combination. DRB by itself decreases cell viability in the absence of growth factors or serum. In these experiments viability was assayed by neutral red uptake by using an automated microplate reader. Inhibition of protein synthesis with cycloheximide (CHX, 1 or 5 micrograms/ml) over a 20-hour period was associated with decreased survival of cells protected by IGF-1 + EGF or PDGF + EGF + IGF, but also with decreased survival of cells incubated in the absence of growth factors or serum. The decrease in survival was somewhat more marked when IGF + EGF was present than when PDGF + EGF + IGF-1 was present. Insulin (1,500 ng/ml) mimics the action of IGF-1 (40 ng/ml). The cell survival-enhancing activities of growth factors are concentration dependent. The evidence presented indicates that PDGF, EGF, and IGF-1 (or insulin) act through distinctive mechanisms in affording protection of cells against death. The short-term protective effects of the growth factors are independent of gene expression and may be mediated via metabolic events. Long-term protection may be dependent on gene expression, especially in the case of IGF-1 + EGF.

Daudi cells, and IFN-sensitive and -resistant Daudi subclones contain 2,300 (Kd=20 pM), 3,700 (Kd=52 pM), and 3,000 (Kd=45 pM) homogeneous IFN-α binding sites per cell, respectively. Thus, IFN-sensitive and — resistant Daudi cells have similar numbers of high affinity IFN-α receptors. The dissociation of IFN from its receptor on each Daudi cell line was resolved into fast and slow components. IFN-α dissociated from IFN-sensitive Daudi cells more slowly than from resistant cells. Also, a greater amount of the IFN-receptor complex becomes associated with the Triton-insoluble cytoskeletal matrix in the sensitive than in the resistant cells. Lectins, which increase the formation of Triton-insoluble IFN-receptor complexes in sensitive and resistant cells, decrease the dissociation of IFN-α from its receptor. Finally, IFN-α inhibits the anti-Ig-induced redistribution of surface Ig in IFN-sensitive but not in IFN-resistant cells. Our results suggest that association of IFN-receptor complexes with the Triton-insoluble matrix may be of functional significance. Such interaction may slow the dissociation of IFN-α from its receptor, impair mobility of cell surface receptors, and perhaps play an important role in transmembrane signalling through the IFN receptor.

Addition of rat interferon-alpha (IFN-alpha) to Fujinami sarcoma virus-transformed rat 3Y1 cells progressively inhibited fluid-phase pinocytosis [10% inhibition at 3 h; maximal (60%) inhibition by 12 h]. Electrophoretic analysis of the cytoskeletal fraction from cultures exposed to IFN for 24 h revealed a novel 76,000-dalton protein (CKp76). The kinetics of its appearance paralleled the inhibition of fluid-phase pinocytosis. CKp76 was not detected in cultures pretreated with actinomycin D, or prelabeled with [35S]methionine, prior to IFN addition. However, the presence of cycloheximide during incubation with IFN had no effect on the synthesis of CKp76 after removal of both agents. These results suggest that the appearance of CKp76 was due to enhanced transcription of its gene in response to IFN. Subcellular fractionation revealed the presence of induced CKp76 in the nuclear pellet. From these results it is possible that CKp76 may be responsible at leat in part for the effects of IFN on fluid-phase pinocytosis.

Regions associatedwith cell-substratumcontactor attachment in Rous sarcoma virus(RSV)-transformedratfibroblasts (RR1022 cells)were identifiedby reflection-interference microscopy.Electronmicroscopy ofsuch regionsrevealedthepresenceofdiscretemembrane- associatedstructurescomposed of a paracrystallinelatticeof hexagons and pentagons to which actin filamentsappear to be attached. Stainingof actin by biotin-labeledheavy meromyosin showed thattransformed cells,unlikenormal fibroblasts, lackprominent actin fibers,and that,instead,much of the fluorescenceisconcentrated inlocicorresponding to locationsoftransientassociationbetween thecelland the substratum.Instationarycells,such lociwere found in rosetteformation,predominantly inthe regionbeneath the nucleus.In cellsengaged inactivemovement, such asduringmigrationintoawound, theactin-containing spotswere concentrated inthe regionofthe leadingedge.A similarpatternof stainingwas observed with antibodytogelsolin, a 91,000-daltonCa'-dependent actinfilament-shortening protein.Since the actionof gelsolinon actinisreversibleand dependent on physiologically relevantchanges incalcium concentration,the localizationof gelsolin,togetherwith actin- bundling proteinssuch as a-actinin,in the regions containingmany small microfilament bundles on the ventralsideof cytoplasm suggeststhatgelsolinmay be a component of the mechanism forthe disassemblyand assembly ofactinduringthe dissolutionand reformation ofstructuresforcell-substratumcontactduringcelllocomotion.Regulationofgelsolinactivity was not dependent on proteinphosphorylation,as shown by lackof "P-incorporationinto gelsolinineithertransformedornormal fibroblasts .

Treatment of three lines of tumor cells (epidermoid carcinoma: HeLa-S3, and Burkitt's lymphoma: Daudi and P3HR-1) with human alpha or beta interferon (HuIFN-alpha or HuIFN-beta) results in inhibition of cell proliferation as well as in increased modal cell volume and heterogeneity of the populations with respect to cell volume. In all three cell lines the IFN-alpha- or IFN-beta-induced changes in cell proliferation and in cell volume are inversely related to each other. However, these lines differ significantly in their sensitivity to the effects of IFN-alpha and IFN-beta.

ABSTRACT Interferon treatment alters the structure of the plasma membrane and the cytoskeleton in a variety of cells. These structural changes are associated with modulation of specific functions in human epidermoid carcinoma (HeLa-S3) cells, human skin fibroblasts (FS-4 and ME), transformed mouse fibroblasts (L-929), and thioglycolate-elicited mouse peritoneal macrophages, all treated with homologous beta interferon. The rigidity of the plasma membrane lipid bilayer is increased within 30 min from the beginning of treatment of HeLa cells growing in suspension, but returns tc control level within a few hr. The rigidity increases again by 24 hr after beginning of treatment and persists. Increased abundance of submembranous actin filaments in interferon-treated HeLa-S3 cells is associated with impairment of the mobility and the endocytosis of receptor-bound concanavalin A, slowing of cell proliferation, increased cell size, and increased frequency of multinucleated cells. In interferon-treated human fibroblasts, increased organization of actin-containing microfilaments into bundles is associated with decreased cell locomotion, membrane ruffling, and intracellular movement of organelles, with prolongation of the intermitotic interval, increased cell size, and increased frequency of abortive mitosis giving rise to multinucleated cells. Increased organization of microfilaments in mouse L-929 cells is associated with a marked rise in the frequency of abortive mitoses.

DNA fiber autoradiography was used to analyze the spatial and temporal organization of activated initiation sites for DNA replication in mouse L929 cells infected with reovirus type 3 (Dearing strain) and in uninfected control cells. Cells were labeled for 10 min with3H-thymidine at high specific activity followed by 3 h of low specific activity labeling. Reovirus infection causes no change in the rate of replication fork progression, but increases both the mean distance between activated initiation sites by ∼ 30% and the nonrandomness in the spatial distribution of the sites along the DNA fibers. Significant synchronization of initiation in adjacent activated sites was detected on DNA fibers from uninfected cells and from reovirusinfected cells. The mean relative initiation time for pairs of initiation events which had occurred prior to high specific activity labeling did not differ significantly between the infected and uninfected cells. The data are consistent with the interpretation that reovirus infection shuts off initiation sites in a coordinated fashion, possibly by preventing activation of entire clusters of potential initiation sites.

Interferon treatment impairs the ability of cells to redistribute cell surface receptors for concanavalin A (Con A). The effect of interferon becomes evident within 3-6 h and is maximal within 36-48 h. Highly purified human fibroblast interferon (> 2 x 10(8) U/mg of protein sp act; concentration; 640 U/ml) caused approximately 85% inhibition of capping of fluorescein-conjugated Con A in interferon-sensitive HeLa-S3 cells at 36 h from the beginning of treatment.

This chapter brings together in a systematic way the recent work as well as some of the earlier studies on the mode of action of halogenated ribofuranosylbenzimidazoles on cellular and viral biosynthesis. Investigations of the cellular and viral biosynthesis, in which these compounds have been used as exploratory tools are also reviewed in this chapter. Compounds in this class of benzimidazoles possess the unique biological activity of selective inhibition of the synthesis of nuclear heterogeneous RNA (hnRNA) in cells of cold-blooded animals, including insects and in cells of avian and mammalian species. Because of the universality of the synthesis of hnRNA in animal species and because a portion of hnRNA sequences becomes mRNA, the action of halobenzimidazole ribosides on cellular biosynthesis is of broad interest. The action of these derivatives is also relevant to the process of transcription of the viral genomes of certain RNA and DNA viruses. In addition, this chapter briefly discusses three groups of structurally distinct bcnzimidazolcs that possess biological actions entirely different from those of halobenzimidazole ribosides: 2-(α-hydroxybenzyl) benzimidazole and certain related compounds are selective inhibitors of picornavirus multiplication; 5-methyl-2-D-ribobenzimidazole and congeners and 5-hydroxy-l-methylbenzimidazole and certain related compounds restore the capacity of chorioallantoic membranes from older chicken embryos to produce influenza virus in high yield.