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T Alper

Publications and source records attributed to T Alper.

At least 19 recordsLinked to original sources
PubMed1992

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

Scrapie, the prototype of a group of diseases which have the unique property of being both hereditary and infectious, is also exceptional in that it fails to evoke an immune response. Purification of crude scrapie preparations revealed a strong association of infectivity with a membrane protein ('PrPsc'); but a protein with the same amino acid sequence ('PrPc') was subsequently also found in normal mammalian nervous tissue. It is postulated by some investigators that 'PrPsc' is itself the infectious agent, or the most important part thereof, but in papers making that proposal immunological aspects have not been addressed. Experimental evidence supporting the hypothesis of a membrane fragment as agent has likewise lately not been taken into account. A modified form of the membrane hypothesis could account for immunological as well as genetic aspects of these diseases.

Animals↗
PubMed1989

The role of repair in radiobiology.

Apart from cancer and mutation induction, radiobiological effects on mammals are mostly attributable to cell 'death', defined as loss of proliferative capacity. Survival curves relate retention of that capacity to radiation dose, and often manifest a quasi-threshold ('shoulder'). The shoulder is attributable to an initial mechanism of repair ('Q-repair') which is gradually depleted as dose increases. Another form of repair, which is not depleted ('P-repair'), increases the dose required to deliver an average of one lethal event per cell (dose 'D0'). Neither form of repair can unambiguously be linked with repair of defects in isolated DNA. An important initial lesion may well be disruption of the complex structural relationship between the DNA, nuclear membrane and associated proteins. One form of P-repair may be restoration of that structural relationship.

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PubMed1987

The cell as single-hit detector.

The common manifestation of shoulders to survival curves, particularly for mammalian cells, has diverted attention from the importance of single-hit action as a radiobiological mechanism. Exponential survival is diagnostic for that mode of action. Of various interpretations of shouldered curves, the one best fitted by experimental facts is that single energy deposits can indeed be lethal; but many cells have capacity for a specific type of repair that is depleted, in a dose-dependent manner, until it ceases to function. The curve then assumes its exponential 'tail'. Genomic DNA seems an obvious target for the scoring of lethal hits. But a body of evidence indicates the presence in the cell of a second, chemically different, target, one in which oxygen interacts at the sites of energy deposits to fix damage, so causing radiosensitization. The nuclear membrane is a likely candidate. In cells proficient at repairing DNA, and irradiated with oxygen present, only a minority of lethal events are attributable to energy deposited in DNA. The hypothesis that hits are scored by .OH, based to a large extent on the phenomenon of chemical protection, is not justified by all the facts and is in conflict with some experimental observations. On the other hand, e-aq may well be damaging to DNA unless oxygen is present to act as scavenger.

Animals↗
PubMed1986

High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation.

When mammalian cells are irradiated in vitro, the component cells of a normal-appearing survivor colony or clone are commonly thought to have proliferative capacity equivalent to that of the unirradiated cells. We have found, however, that cells appearing in survivor colonies may carry heritable lethal defects which come to light, perhaps only after numerous successful divisions, in the form of plating efficiencies that are reduced below those of unirradiated cells in a dose-dependent manner. We regard these heritable defects as signs of the induction of lethal mutations, which, like non-lethal mutations, may require many generations before they are expressed. This effect has been noted in two very dissimilar mammalian cell lines, one a primary culture from adult tissue, the other an immortal cell line. We suggest that induction of lethal mutations may occur also in somatic cells in vivo; this would account for the well-known observation that previously irradiated but apparently healed tissue is subsequently proved to be extraordinarily sensitive to subsequent exposure to irradiation or cytotoxic drugs. The results of our experiments in vitro suggest that current methods of estimating mutation or transformation yields may yield underestimates. If lethal mutations are induced also in vivo, interpretations of the results of fractionation experiments on normal tissues may have to be reconsidered.

Animals↗
PubMed1978

The scrapie agent: evidence against its dependence for replication on intrinsic nucleic acid.

Exposure of the scrapie agent to u.v. light at various wavelengths has shown that light of 237 nm is 4 to 5 times as effective in inactivating it as 'germicidal' wavelengths (250 to 270 nm); whereas with systems that depend on RNA or DNA for function, inactivation is most effective by wavelengths in the germicidal range and there is a minimum of response in the wavelength region round 240 nm. The action spectrum for the scrapie agent is reminiscent of the absorption spectrum for purified bacterial endotoxin, identified as a lipopolysaccharide complex. Dilute aqueous suspensions of scrapie agent were exposed to ionizing radiations in the presence or absence of oxygen. In dilute suspensions of test systems depending on the integrity of nucleic acid or protein, oxygen is almost invariably protective, but it was extremely sensitizing for inactivation of the scrapie agent, to an extent approached only in the case of membranous systems like lysosomes. Results of these two methods argue against dependence of the scrapie agent on an intrinsic nucleic acid moiety for ability to replicate. They suggest that a lipid fraction is an important component and to that extent provide additional support for the 'membrane hypothesis'.

Animals↗
PubMed1977

The role of membrane damage in radiation-induced cell death.

Radiation-induced cell death is probably mediated primarily through deposition of energy, in single events, in a few vital macromolecules, or targets, the integrity of which is indispensable for proliferation. The genome is customarily regarded as the main target, but several lines of evidence support the inference that there are important consequences of events in nuclear membranes in eukaryotes, and plasma membrane in bacteria. The identification of a target depends to some extent on parallelism between modifications of biological damage to putative targets and to the cell as a whole. An important modifying procedure is removal of oxygen from the irradiated system. The presence of oxygen almost always sensitizes cells, but when model systems with biological function are irradiated extra-cellularly a high degree of sensitization by oxygen has been observed only with those in which membrane function is important. This makes sense because the lipid content of membranes renders them readily peroxidizable. When the quality of the radiation is changed, its effectiveness changes in opposite directions for subcellular model targets and for cells. This could be accounted for if interactions between lesions in membranes and in attached DNA play a substantial role in cellular radiation effects.

Animals↗
PubMed1975

A marked dependence of the comparative effectiveness of neutrons on tumour line, and its implications for clinical trials.

The responses of five transplantable rat tumour lines to neutron and X irradiation have been compared by a method in which radiation-induced delay in tumour growth is used as a measure of effect. All the tumours were sarcomas and were irradiated at the same size, after growth in the same site, and under standard conditions. This group of similar tumours exhibited a large range in values of RBE in a dose range within which fractions of hypoxic cells did not detectably influence the result of X irradiation. Of the five tumour lines used, there were two pairs the members of which had a common origin and were histologically similar; the greatest differences in RBE values were between members of the pairs. These results suggest that the therapeutic use of high LET radiation cannot be expected uniformly to achieve local control better than conventional treatment of tumours at a given site, or even of a given histological type. Research is needed into methods that will have predictive value for the relative success of neutron therapy.

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