The dose-response relationships for myeloid leukemia and malignant lymphoma in BC3F1 mice

The present analysis of data on the induction of lymphoma and myeloid leukemia in BC3F1 mice has indicated some new and interesting aspects regarding the shapes of the dose-effect curves. The incidence data can be interpreted by radiobiological models of the induction process coupled with cell inactivation. In particular, for malignant lymphoma the dose-response curve after X rays can be described assuming a quadratic model corrected for cell inactivation, while the incidence data after fission neutrons are best fitted by a linear model which also allows for cell inactivation. Myeloid leukemia has also been induced in BC3F1 mice. The bell-shaped dose-response curves observed after irradiation with either X rays or neutrons are explained by assuming simultaneous initial transforming events and cell inactivation with the data for cell inactivation at higher doses being in agreement with data reported for other strains of mice. A value for relative biological effectiveness of 4 is obtained at the lowest neutron dose used. The value of the inactivation parameters can be compared with those of the cell inactivation probability per unit dose for the bone marrow hematopoietic stem cells, which are believed to be the target cells for these tumors.     

Model of calcium channel inactivation: a qualitative analysis

A simple model of calcium channel inactivation has been developed, based on the accumulation of calcium ions at the inner mouth of the channel and on their binding to a receptor which inactivates the channel. A qualitative analysis has shown that upon an appropriate choice of parameters corresponding to the cell structure and to kinetic properties of its components, the calcium dependent inactivation and that assumed to be voltage dependent can both be emulated. The model suggests that the supposed variety of calcium channels might be explained by quantitative differences in nonlinear interactions of the channels with other cell components.     

Conditional probability analysis for a domain model of Ca(2+)-inactivation of Ca2+ channels.

The domain model of Ca2+ inactivation of Ca2+ channels, which has been used to explain rapid inactivation of whole cell Ca2+ currents in pancreatic beta cells, is applied to single-time and conditional open probability measurements on guinea pig ventricular myocyte Ca2+ channels. These two measurements greatly constrain the choice of kinetic constants in the model. Calculations with the model provide a simple quantitative explanation of recent experimental results, including a slow increase in the inactivation rate.     

Gene Expression and Pathway Analysis of Effects of the CMAH Deactivation on Mouse Lung,Kidney and Heart

BackgroundN-glycolylneuraminic acid (Neu5Gc) is generated by hydroxylation of CMP-Neu5Ac to CMP-Neu5Gc, catalyzed by CMP-Neu5Ac hydroxylase (CMAH). However, humans lack this common mammalian cell surface molecule, Neu5Gc, due to inactivation of the CMAH gene during evolution. CMAH is one of several human-specific genes whose function has been lost by disruption or deletion of the coding frame. It has been suggested that CMAH inactivation has resulted in biochemical or physiological characteristics that have resulted in human-specific diseases.Conclusions/SignificanceMice bearing a human-like deletion of the Cmah gene serve as an important model for the study of abnormal pathogenesis and/or metabolism caused by the evolutionary loss of Neu5Gc synthesis in humans.     

The use of immunological tolerance to investigate B lymphocyte replacement kinetics in chickens

A simple mathematical model has been derived, describing the irreversible inactivation of immature B cells by high doses of antigen during induction of tolerance, and the antigen-independent replacement of B cells by differentiation of their precursors. The latter leads to recovery from tolerance, the rate of which can be used to assess the rate of B cell replacement in experiments. The model has been compared with experimental tolerance to human albumin in newly hatched chickens.(1) It has been shown that this tolerance cannot be explained only by elimination of B cells but (2) the computed rate of B cell replacement agreed with the experimental rate assessed by immunization of tolerant chickens with a cross-reacting antigen. (3) In order to further verify the model, additional experiments to test the rate of B cell replacement were suggested by the model.     

Cell inactivation by ionizing particles and the shapes of survival curves

Recent experiments concerning the survival of monolayer cells irradiated by different parts of ion Bragg peaks opened a way to a deeper mechanistic understanding of cell inactivation. A new theoretical formula for survival curves has been derived reflecting two basic phases of the given mechanism, i.e. energy transfer to a cell nucleus and subsequent biological effect (depending on the amount of imparted energy). The survival ratio for a given dose has been expressed as a function of inactivation probabilities of individual cells after different numbers of nucleus hits (a given amount of energy being transferred to a cell nucleus in each ion traversal). Having used the experimental data for V79 cells irradiated by protons, deuterons and helium ions in different parts of Bragg peaks preliminary values of these inactivation probabilities for individual cells at different LET values have been established.     

The auxin-binding protein 1 is essential for the control of cell cycle

The phytohormone auxin has been known for >50 years to be required for entry into the cell cycle. Despite the critical effects exerted by auxin on the control of cell division, the molecular mechanism by which auxin controls this pathway is poorly understood, and how auxin is perceived upstream of any change in the cell cycle is unknown. Auxin Binding Protein 1 (ABP1) is considered to be a candidate auxin receptor, triggering early modification of ion fluxes across the plasma membrane in response to auxin. ABP1 has also been proposed to mediate auxin-dependent cell expansion, and is essential for early embryonic development. We investigated whether ABP1 has a role in the cell cycle. Functional inactivation of ABP1 in the model plant cell system BY2 was achieved through cellular immunization via the conditional expression of a single-chain fragment variable (scFv). This scFv was derived from a well characterized anti-ABP1 monoclonal antibody previously shown to block the activity of the protein. We demonstrate that functional inactivation of ABP1 results in cell-cycle arrest, and provide evidence that ABP1 plays a critical role in regulation of the cell cycle by acting at both the G1/S and G2/M checkpoints. We conclude that ABP1 is essential for the auxin control of cell division and is likely to constitute the first step of the auxin-signalling pathway mediating auxin effects on the cell cycle.     

A slide rule for deriving the rate equations of enzyme catalysed reactions with unbranched mechanisms

It has been proposed that mRNA stability in Escherichia coli is enhanced by association with ribosomes and that failure of ribosome initiation into polysomes results in message inactivation. This hypothesis is examined with the aid of a simple steady queuing model from which mRNA lifetimes and other cell parameters may be calculated. Agreement with experimentally determined lifetimes is good.     

The ultraviolet light and photosensitized inactivation of tobacco mosaic virus

The quantum yield for the inactivation of tobacco mosaic virus has been determined at 253.7 mµ and found to be 4.3 x 10^–6. The possible significance of the observed one-hit process of inactivation has been discussed in terms of the kinetics and the rupture of model substances including nucleic acid. The ultraviolet light inactivation, which proceeds independent of oxygen, occurs without change in physicochemical properties, with the possible exception of an enhanced sensitivity to thermal denaturation. The photosensitized inactivation of virus by acriflavine has been found to proceed parallel with the destruction of the dye. The action was found to be dependent upon adsorbed dye, and the inactivation is enhanced by the presence of oxygen.     

The Xenopus Cell Cycle: An Overview

Oocytes, eggs and embryos from the frog Xenopus laevis have been an important model system for studying cell-cycle regulation for several decades. First, progression through meiosis in the oocyte has been extensively investigated. Oocyte maturation has been shown to involve complex networks of signal transduction pathways, culminating in the cyclic activation and inactivation of Maturation Promoting Factor (MPF), composed of cyclin B and cdc2. After fertilisation, the early embryo undergoes rapid simplified cell cycles which have been recapitulated in cell-free extracts of Xenopus eggs. Experimental manipulation of these extracts has given a wealth of biochemical information about the cell cycle, particularly concerning DNA replication and mitosis. Finally, cells of older embryos adopt a more somatic-type cell cycle and have been used to study the balance between cell cycle and differentiation during development.     

Activation of Notch Signaling Is Required for Cholangiocarcinoma Progression and Is Enhanced by Inactivation of p53 In Vivo

Cholangiocacinoma (CC) is a cancer disease with rising incidence. Notch signaling has been shown to be deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of CC is still not fully explored. In this study, we investigated the effects of Notch inhibition by γ-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53. GSI IX treatment effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics. Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo.     

Mechanisms of antibiotic resistance and tolerance in Streptococcus pneumoniae

Streptococcus pneumoniae is a major pathogen causing potentially life-threatening community-acquired diseases in both the developed and developing world. Since 1967, there has been a dramatic increase in the incidence of penicillin-resistant and multiply antibiotic-resistant pneumococci worldwide. Prevention of access of the antibiotic to the target, inactivation of the antibiotic and alteration of the target are mechanisms that S. pneumoniae has developed to resist antibiotics. Recent studies on antibiotic-tolerant pneumococcal mutants permitted development of a novel model for the control of bacterial cell death.     

Cholesterol-dependent gramicidin A channel inactivation in red blood cell membranes and lipid bilayer membranes

The exchange diffusions of tracer cations (22Na+, 86Rb+) are studied on gramicidin-A-treated red blood cell (RBC) membranes. A time-dependent decrease in cation permeability has been observed and has been considered to be the result of a channel inactivation process. The channel inactivation appears at 20 and 30 degrees C but not at a temperature as low as 6 degrees C. The gramicidin A channel inactivation can be monitored by a conductivity decay of molecular lipid membranes (BLM) prepared either from cholesterol or from a mixture of cholesterol and phospholipids but not of pure phosphatidylethanolamine. The role of cholesterol in the channel inactivation is discussed.     

The substructure of phosphodiesterase as established by radiation inactivation: A reinterpretation of results

A model for the activation of phosphodiesterase by calmoduling based on a conversion of inactive dimers to active monomers, derived from radiation inactivation studies J. Biol. Chem. (1981) 256, 11351–11355 has been re-examined using a simple probability argument. We conclude that the original model is not supported by the radiation inactivation studies, since our analysis of this model would predict that the rate of radiation inactivation of calmodulin-dependent phosphodiesterase activity be exactly twice that for the decay in total activity in marked contrast with the results obtained.     

Gene mutations, chromosome aberrations and survival after the x-ray irradiation of a Chinese hamster cell culture protected by cysteamine

The protective effect of cysteamine against 6-thioguanine-resistance (TCr) mutations, chromosome aberrations and inactivation caused by X-ray in cultured cells of Chinese hamster (clone 431) has been studied. The dose-effect curves have been obtained under irradiation condition without protector and with it. Dose-modifying factor of 2 was calculated for chromosome aberrations and cells inactivation and 2,8 for TCr mutations. It is supposed that the cysteamine acts on the general mechanisms involved in damages realization which results in gene mutations, chromosome aberrations and cell inactivation.     

The EPR properties of nickel in hydrogenase from Methanobacterium

A model for the activation of phosphodiesterase by calmoduling based on a conversion of inactive dimers to active monomers, derived from radiation inactivation studies J. Biol. Chem. (1981) 256, 11351–11355 has been re-examined using a simple probability argument. We conclude that the original model is not supported by the radiation inactivation studies, since our analysis of this model would predict that the rate of radiation inactivation of calmodulin-dependent phosphodiesterase activity be exactly twice that for the decay in total activity in marked contrast with the results obtained.