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A new model which imitates the behaviour of an alive organism is described. The paper provides a new answer to the question: what are life and death? The dependences of lifetime of mammals on the embryo mass and the body mass are found. The connection between the lifetime of an alive organism and the metabolic rate is described.
UNLABELLED: In radioimmunotherapy, the treatment of bulk tumors by radionuclides that emit energetic beta particles is the preferred approach. However, for the eradication of small clusters of cancer cells, radionuclides that emit Auger electrons or alpha particles are considered to be advantageous because of their ability to deposit radiation energy locally. If such radionuclides are internalized by the cells, the total dose to the cell nuclei is thought to be primarily determined by the self-dose (dose to cell nucleus from activity within the cell) in comparison to the cross-dose (dose to the cell nucleus from activity in all other cells). METHODS AND RESULTS: The self-dose-to-cross-dose ratios to the cell nucleus were calculated for different cluster sizes (26-400 microns) with monoenergetic electron and alpha particle sources distributed uniformly in different cell compartments (cell surface, cytoplasm, nucleus). Model calculations were also performed for several radionuclides (Auger, beta and alpha emitters). Absorbed fractions for sources of monoenergetic electron and alpha particles, distributed uniformly in small spheres (26-5000 microns), were also calculated along with S-values for a number of radionuclides. CONCLUSIONS: When most of the cells in the cluster are labeled with beta or alpha emitters, the cross-dose component of the total dose is important irrespective of cluster size and subcellular source distribution and increases as the cluster size increases. The self-dose is always important for Auger emitters. When the self-dose is negligible, the mean absorbed dose to the cell nuclei is well represented by the mean dose to the micrometastasis.
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Platelet activation as a result of vascular injury provokes endothelial cells to respond in a manner which limits or reverses the occlusive consequences of platelet accumulation. If the agonistic forces are strong, platelet accumulation is irreversible. In vitro data from our laboratory have repeatedly demonstrated that platelets become unresponsive to all agonists when in proximity to endothelial cells. This unresponsiveness is due to at least three separate endothelial "thromboregulatory" systems: eicosanoids, endothelium-derived relaxing factor (EDRF/NO), and most importantly an endothelial cell ecto-nucleotidase which metabolizes released platelet adenosine diphosphate (ADP) with consequent restoration of platelets to the resting state. This nucleotidase is operative in the complete absence of EDRF/NO and eicosanoids, indicating that the latter two are dispensable thromboregulators. We have solubilized the human endothelial cell ectoADPase, as well as that from placental tissue. Candidate proteins from a purified ADPase fraction are now being studied in further detail. An understanding of the molecular biology of the ADPase gene may lead to development of therapeutic agents such as soluble forms of the enzyme as well as approaches toward up-regulation of ectoADPase activity. This could result in "early thromboregulation", i.e. prevention and/or reversal of platelet accumulation at sites of vascular damage via immediate metabolic removal of the prime platelet agonist-ADP.
An experimental acute liver injury model can be produced by the injection of bacterial lipopolysaccharide (LPS) into Propionibacterium acnes (P. acnes) pretreated rats. The massive liver cell necrosis is estimated by elevation of serum transaminase activities. In this study, we produced this necrosis in an in vitro model by using primary co-cultured rat liver cells. A novel method for the preparation of spheroids consisting of P. acnes pretreated parenchymal and nonparenchymal liver cells has been successfully developed quickly by the rotary culture system within 24 hr although it takes 7 days to form the spheroid using a collagen-conjugated thermo-responsive polymer such as a cell substratum. Clear elevations of transaminase activities, TNF-alpha and CINC-1/gro/KC leaked from these spheroids into the medium caused by the exposure of 10 microgram/ml LPS for 48 hr were observed. These results suggest that this rotary co-culture system of rat liver cells is a useful model as an alternative to animal tests for fulminant hepatitis.
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EGF has been reported to stimulate thyroid cell proliferation. In the present study we investigated the effects of anti-EGF-R-antibody (Mab 4253 both as monolayers and spheroids of an oxyphilic, non iodine metabolizing, papillary thyroid carcinoma cell line (ONCO-DG-1) and roughly characterized their EGF-R. Scatchard analysis with I-125-labeled-EGF demonstrated a low number of 1.5 x 10(4) EGF-R per monolayer cell (KD 4.1 X 10(-10) M) and only 6 x 10(3) EGF-R per spheroids cell (KD 5.0 X 10(-10) M). Already 80% of the binding sites were blocked by only 0.44 microgram/ml Mab 425. Proliferathe activity and EGF-R were found to be regularly distributed throughout the spheroids. Adding Mab 425 to medium containing 1 ng/ml EGF, inhibited the growth of monolayer cells by 15% (1 ng/ml Mab 425) and 28% (10 ngiml Mab 425), measured by the MTT-test. The volume growth of spheroids was inhibited by 10-15% using 2 micrograms/ml Mab 425, whereas their viability (MTT-Test) was almost identical. The results show that the anti-EGF-R-antibody (Mab 425) alone is not effective enough for therapeutical use, but it could be of clinical value in conjugation with radionuclides (e.g. I-131) in order to reach metastases not metabolizing iodine.
Functional and structural aspects of intercellular interactions are considered. Chemical substances are universal mediators of intercellular interactions. Electrical and mechanical interactions are also involved in cell-cell cooperation. Functional peculiarities of the two principal types of intercellular interactions-ligand-receptor interactions and interactions based on permeable contacts-are compared. Examples of basic tissue processes are given (such as the mechanisms of embryonic induction and differentiation, regulation of cell proliferation, temporal and spatial regulation of the activity of differentiated cells, interactions between excitable cells) to illustrate the notion that the types of intercellular interactions are mutually complementary and fulfill different functions. Ligand-receptor interactions predominantly provide signal functions and ensure intertissue interactions, while the interactions based on permeable contacts mainly fulfill intratissue coordination relying on positional information and the exchange of energy and matter.
We have found that a murine hepatoma displays a considerable phenotypic diversification in culture, which depends upon the substratum utilized, and is manifested by the formation of multicellular structures of differing geometry: Monolayer on glass and plastic, thick multilayer pads on Gelfilm, and spheroids on agar and agarose. These multicellular morphological phenotypes were assayed without disruption to ascertain their antigenicity in vitro and their tumorigenicity in vivo and to obtain quantitative information on the effect of the spatial arrangement of the hepatoma cells upon the ability of each multicellular structure to interact, as a whole, with molecules and cells in its surroundings. The antigenicity of the multicellular structures was determined with calibrated probes and a methodology that measures the total antigenicity, as well as antigenicity per unit of surface area. Antigenicity was found to differ in the following decreasing order: Monolayer on plastic greater than spheroids on agarose greater than spheroids on agar greater than multilayer on Gelfilm. At least part of these antigenic variants arise from different degrees of masking of the structures' surface determinants by a trypsin-sensitive material. The multicellular phenotypes also differed in tumorigenicity. When assayed in syngeneic hosts under comparable conditions, agar-grown spheroids produced the fewest tumors, whereas Gelfilm-grown multilayers produced the most. These two independent sets of data show that the various geometries that a tumor tissue is induced to acquire by the culture substratum are accompanied by a distinctive combination of surface and biological properties.
A key step in the development of all multicellular organisms is the differentiation of specialized cell types. The eukaryotic microorganism Dictyostelium discoideum provides a unique experimental system for studying cell-type determination and spatial patterning in a developing multicellular organism. Unlike metazoans, which become multicellular by undergoing many rounds of cell division after fertilization of an egg, the social amoeba Dictyostelium achieves multicellularity by the aggregation of approximately 10(5) cells in response to nutrient depletion. Following aggregation, cell-type differentiation and morphogenesis result in a multicellular organism with only a few cell types that exhibit a defined patterning along the anterior-posterior axis of the organism. Analysis of the mechanisms that control these processes is facilitated by the relative simplicity of Dictyostelium development and the availability of molecular, genetic, and cell biological tools. Interestingly, analysis has shown that many molecules that play integral roles in the development of higher eukaryotes, such as PKA, STATs, and GSK-3, are also essential for cell-type differentiation and patterning in Dictyostelium. The role of these and other signaling pathways in the induction, maintenance, and patterning of cell types during Dictyostelium development is discussed.
Single heart cells were obtained from frog ventricle using an enzymatic dispersion technique. The whole cell variation of the patch clamp technique was used to monitor action potential and cell membrane currents. The clamp circuit could be switched electronically between voltage and current clamp modes. The effects of seal leakage currents were to depolarize the cell, reduce the amplitude of the plateau, and lengthen the action potential duration. A scheme to compensate for these currents is presented. The membrane currents obtained from the single cell under voltage clamp conditions were compared to those obtained from multicellular preparations using the single sucrose gap technique. Hyperpolarizing clamps showed time-dependent, depletion-related K+ currents for the multicellular preparation, whereas for the single cell no such currents were observed. The absence of extracellular accumulation or depletion of K+ in the single cell was confirmed by the lack of post-clamp afterpotentials or changes in resting potential following a train of frequently elicited action potentials. The TTX-insensitive inward current was relatively faster in the single cell, compared to that measured in the multicellular preparation. A delayed time-dependent outward current was observed in the positive potential range for both single and multicellular preparations. The isochronal current-voltage (I-V) relations obtained at 400 ms were N-shaped for both preparations, but was more negative for the single cell at potentials positive to -20 mV. The results indicate a strong similarity between membrane currents obtained in single and multicellular preparations. The differences in the currents in the two preparations are due in large part to accumulation or depletion of K+ in the extracellular space.
BACKGROUND: Although coronary stenting has decreased the high restenosis rate associated with percutaneous transluminal coronary angioplasty of chronic total occlusions (CTOs), the results are still less satisfactory than those found in nonoccluded lesions, at least as reported with the Palmaz-Schatz stent. The present work compares the restenosis rate of other stent designs with that of the Palmaz-Schatz stent. METHODS: We studied the long-term angiographic outcome of 120 CTOs successfully recanalized with balloon-expandable stents and without concomitant debulking techniques. Angiographic follow-up and full quantitative coronary angiography analysis was prospectively performed in all patients. Three different stent designs were compared: Palmaz-Schatz (n = 47), coil (n = 24), and multicellular (n = 49). Particular attention was paid to their performance in vessels of 3 mm or less and greater than 3 mm in diameter. Restenosis was defined as a 50% or greater diameter stenosis at follow-up. RESULTS: Multicellular stents were implanted more frequently in the left anterior descending artery and in patients with multivessel disease. No other significant differences in clinical or angiographic baseline characteristics, including vessel size, were noted between groups. At follow-up, multicellular stents presented a lower restenosis rate (22% vs 36% and 58% in the Palmaz-Schatz and coil stent groups, respectively; P =.01 ) and larger minimal luminal diameters (1.92 +/- 0.85 mm vs 1.73 +/- 0.98 and 1.38 +/- 0.83 mm in the Palmaz-Schatz and coil stent groups, respectively; P = 0.0). The superiority of the multicellular stent design resulted from a lower restenosis rate in vessels of 3.0 mm or less in diameter (20% vs 47% and 79% in the Palmaz-Schatz and coil stent groups, respectively; P =.006). CONCLUSIONS: These results suggest that the restenosis rate after stent recanalization of CTOs is influenced by both stent design and vessel size and may indicate a superiority of multicellular over Palmaz-Schatz and coil stent designs for this purpose.
We previously developed a model in which rabbit gall bladder epithelial cells in collagen gels proliferated and formed multicellular spherical cysts after 2 to 4 days. In the present study, we examined in depth the dynamic processes of loss and reestablishment of cell polarity of rabbit gallbladder epithelial cells isolated and cultured in collagen gel. Six hours after being place in culture, the isolated epithelial cells had lost the morphologic features and phenotypic markers inherent in the in vivo gallbladder mucosa, and autophagic vacuoles appeared transiently, reflecting epithelial cell injury, or remodelling, or both. After 12 hours, mucin dots appeared in clumps of epithelial cells and gradually became larger, and the epithelial cell clumps were transformed into multicellular cysts after 1 to 2 days. The luminal surfaces of the mucin dots (intracytoplasmic inclusions or small lumens sealed by several epithelial cells) and multicellular cysts were covered by microvilli and presented profiles of mucus glycoprotein and carbohydrate residues shared with the in vivo gallbladder mucosa. The presence of cellular adhesion structures and the distribution of cellular organelles toward the luminal surface implied the reestablishment of epithelial cell polarity. The addition of cytochalasin B induced many mucin-positive cytoplasmic inclusions covered by microvilli in the epithelial cells of the multicellular cysts, while the addition of transforming growth factor beta 1 promoted maturation of the multicellular cysts. This short term culture is useful for the analysis of the polarity of biliary epithelial cells and for examining disorders in this polarity.
1. The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea-pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. 2. In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE-sepharose chromatography. 3. In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE isoenzymes I-IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3':5'-cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I-IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue. 4. To investigate whether the PDE I-IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3-isobutyl-1-methylxanthine (IBMX), UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl)benzimidazole HCl) and rolipram. UD-CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 mumol l-1) and in ventricular tissue (IC50 value 0.1 mumol l-1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 mumol ml-1) and in ventricular tissue (IC50 1.1 mumol l-1) whereas IBMX was a nonselective PDE inhibitor in both preparations.5. It is concluded that the PDE isoenzymes I-IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I-IV exist in guinea-pig ventricular cardiomyocytes and multicellular ventricular tissue.
This article presents a brief review of stressors, their cellular and intracellular targets, stress proteins, molecular chaperones, and other anti-stress mechanisms. New data are reported on cochaperones and multicellular structures in archaea. The molecular chaperoning systems of bacteria and eukaryotes have been studied for many years and are relatively well known in terms of their components and mechanisms of action, although many details remain to be elucidated and almost certainly other components will be discovered in the future. By comparison, the molecular chaperoning system of archaea is still unexplored. Since archaea have some molecular genetic and physiologic features similar to those of bacteria and some resembling those of eukaryotes, extrapolation from what is known of organisms from these two phylogenetic domains to archaeal species is unwarranted. For example, the components of the molecular chaperone machine, Hsp70(DnaK), Hsp40(DnaJ), and GrpE, in the archaeal species that have it, are closely related to bacterial counterparts, whereas the archaeal chaperonins are like the eukaryotic equivalents. Furthermore, many archaeal species lack the chaperone machine, in contrast to bacteria and eukaryotes that have it without any known exception. A search for the cochaperones trigger factor, Hop, Hip, BAG-1, and NAC in archaeal genomes demonstrated no conserved equivalents, but two families of archaeal molecules were identified that might be related to NAC and Hop, respectively. Multicellular structures with a single species such as packet and lamina are formed by Methanosarcina species, among which the best studied is M. mazeii. Multispecies multicellular structures are formed by a variety of archaeal organisms, which are either flat (biofilm) or globular (granule) and constitute a functional association or consortium. Details of morphology, formation, and internal organization are described for representative examples of multicellular structures. These may be seen as the result of primitive histogenesis reflecting primeval mechanisms of differentiation-development that might have evolved driven by environmental stressors. Cells in these complex threedimensional arrangements are not only positioned so they can interact with each other for more efficient functioning as in a tissue or organ, but are also protected from stressors. Single cells lacking the protective shield of other cells packed together with intercellular connective material, which is typical of multicellular structures, are directly exposed to environmental stressors and, thus, are at a disadvantage from the evolutionary standpoint. It seems reasonable to argue that differentiation-development leading to histogenesis might have arisen in primeval times as a consequence of the harsh conditions that primitive life forms had to endure, and that the ability to form tissue-like structures was a primary characteristic that ensured positive selection.
Evolutionary transitions to new levels of individuality have usually been treated as a part of the "units of selection" problem. It has previously been assumed that the unit of transmission and heritable variation at each level is the same--that it is the DNA base sequence and its variations. It is suggested here that considering the nature and the role of hereditary variations produced by non-DNA inheritance systems is essential for understanding some evolutionary transitions. The argument is illustrated by considering the role of epigenetic inheritance systems (EISs), the systems responsible for cellular memory, in the transition from unicellularity to multicellularity. It is argued that EISs played a vital role in the transition to multicellularity and the evolution of complex ontogenies, as well as having an important effect on the evolution of developmental strategies which protect the multicellular individual from disintegrating into its component parts. An analogy between the transition to multicellularity and the transition to a cultural unit integrated by language is also suggested.
The ultrastructure of sporogenesis was studied in Henneguya laterocapsulata parasitizing the skin of hybrid catfish (Clarias gariepinus x Heterobranchus bidorsalis) in Nigeria. Sporogenesis started when a generative cell was surrounded by a second nondividing cell (i.e., envelope cell). By subsequent divisions of the generative cell, ten cells were produced, which finally became arranged into two spore-producing units. Each unit consisted of a binucleate sporoplasm, two capsulogenic cells, and two valvogenic cells. Apparently capsulogenesis, valvogenesis, and sporoplasm differentiation occurred concomitantly. In research for chemotherapy of fish parasitized by myxosporeans a new triazine derivative, 2-[3,5-alpha-dichloro-4-(4-methyl-sulfonylphenoxy)-phenyl]-1-me thy l- hexahydro-1,2,4-triazine-3,5-dion (HOE 092 V), was tested in vivo against the uni- and multicellular developmental stages of H. laterocapsulata. Naturally infected catfish were incubated in water containing 0, 2.5, 5, and 10 micrograms HOE 092 V/ml or the pure solvent for 3 h. After the fish had been returned into fresh water, they were killed 1 day after the treatment and the plasmodia were studied by means of light and transmission electron microscopy. Starting with a dose of 2.5 micrograms HOE 092 V/ml, the pericyte's outer membrane was broken in the bi- and multicellular stages. The number of ribosomes in the bi- and multicellular stages decreased. In the multicellular stages the rough endoplasmic reticula of the capsulogenic cells were enlarged. Treatment with 5 micrograms HOE 092 V/ml led to breaks in the limiting outer membranes of the capsulogenic cells and to vacuolization of their peripheral cytoplasm. In early prespore stages a decrease in the number of spherical inclusions was recognized.(ABSTRACT TRUNCATED AT 250 WORDS)