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PubMed1991

Characterization of the human beta-thromboglobulin gene. Comparison with the gene for platelet factor 4.

beta-Thromboglobulin (beta TG) is a platelet alpha-granule protein that is released in large amounts following platelet activation. This protein has approximately 70% amino acid identity with another platelet alpha granule protein, platelet factor 4 (PF4), and approximately 30% identity with other members of a family of proteins encoded by the small inducible genes (SIG) that are involved in the overlapping processes of inflammation, wound repair, and coagulation. Thus, the isolated beta TG gene is of interest in that it may further increase our understanding of beta TG's biological role, the regulation of its megakaryocytic-specific nature of expression, and the evolution and divergence of the SIG family. Using a beta TG cDNA isolated from a DAMI cell cDNA library, we cloned the corresponding beta TG gene. The gene is 1,139 base pairs (bp) long, and, like other members of the SIG family, the beta TG gene is divided into 3 exons. Two major transcriptional start sites were defined by primer extension analysis of platelet RNA, and, based on the more commonly used start site, the 5'-untranslated region is 87 bp. A TATA box is present beginning 32 bp upstream to this site. The first exon contains the 5'-untranslated region as well as the signal peptide. The second exon begins 6 bp 3' to the homologous site in PF4, and the third exon begins at a position homologous to that in PF4. Interestingly, the beta TG and PF4 genes have little detectable homology in the flanking or intronic sequences. In particular, a pyrimidine tract 5' to both the rat and human PF4 genes is not present in the upstream region of the beta TG gene. Genomic Southern blot analysis suggests that, as with the PF4 gene, there are multiple copies of the beta TG gene in the human genome. Chromosomal localization using polymerase chain reaction analysis of human/hamster somatic cell hybrids demonstrated that the beta TG gene, like the PF4 gene, is located on chromosome 4. It is, therefore, possible that the beta TG and PF4 gene form a single genomic locus on chromosome 4 whose members become coordinately activated during megakaryocyte differentiation.

Amino Acid Sequence↗

PubMed2002

Salivary gland B cell lymphoproliferative disorders in Sjögren's syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins's lymphomas.

Sjögren's syndrome (SS) represents a pathological model of the evolution from polyclonal B lymphocyte activation to oligoclonal/monoclonal B cell expansion, which may culminate in the development of a malignant lymphoproliferative disease. The different phases of this process are usually marked by the appearance of antigen-driven activated B cell clones, which are commonly IgM-positive and with rheumatoid factor (RF) activity. However, the agent(s) able to trigger B cell proliferation is still unknown. A similar pathogenetic mechanism exist in mixed cryoglobulinemia, another autoimmune disease that often evolves to non-Hodgkin's lymphoma (NHL) and in which hepatitis C virus (HCV) infection has been demonstrated to play an etiopathogenetic role. In the present study, we cloned and sequenced the antigen receptor (IgR) variable region genes of SS-associated monoclonal non-neoplastic lymphoproliferations and compared them with those of our previous reported HCV-associated NHL, to derive clues on the antigen(s) that sustains SS. The results obtained showed remarkable homologies between the antigen combinatory regions of the IgR expressed by both diseases. These homologies concern: a) the specific combinations of heavy and light variable region genes; b) the limited length of complementarity-determining regions (CDR3); c) the homology with antibodies with RF activity; d)the amino acid sequences of CDR3 in which common somatic mutations are present that possibly determine the antigen-binding specificity. In conclusion, although there are significant differences between SS and HCV-associated lymphoproliferative diseases, they share many molecular characteristics, which suggest an immunological cross-reactivity or molecular mimicry among the agents that underlie these disorders.

Adult↗

PubMed2003

Lamina-associated polypeptide 2beta (LAP2beta) is contained in a protein complex together with A- and B-type lamins.

Lamina-associated polypeptide 2beta (LAP2beta) of vertebrates is an integral membrane protein of the inner nuclear membrane that is generated by alternative splicing from the LAP2 gene. In the majority of Xenopus somatic cells including cultured kidney epithelial cells (A6 cells) there is only one major LAP2 isoform expressed that has the highest similarities with the mammalian LAP2beta whereas isoforms corresponding in size to the mammalian LAP2gamma and alpha are not detectable. We selected A6 cells and A6 cells stably expressing GFP fusion proteins of Xenopus LAP2beta (XLAP2Pbeta) as a model system to study interactions between LAP2beta and lamins. In vitro binding experiments with GST-XLAP2beta fusion proteins and immunoprecipitations with antibodies to GFP revealed that XLAP2beta is part of a complex that contains A- and B-type lamins. For the targeting to the nuclear envelope and the in vivo formation of this complex, GFP fusion proteins were sufficient comprising only the carboxyterminal 135 amino acids of XLAP2beta or the comparable region of zebrafish LAP2beta. A highly conserved 36 amino acids long sequence is located in this region of LAP2beta that is part of the lamina-binding domain previously identified in rat LAP2beta. GFP-LAP2beta fusion proteins of Xenopus, zebrafish, and rat that contained this sequence do compete with endogenous LAP2 in transfected cells for the same binding sites in the lamina. Our data indicate that the lamina-binding site of LAP2beta has been highly conserved during vertebrate evolution and suggests that this region of LAP2beta mediates the interactions between polymers of A- and B-type lamins.

Amino Acid Sequence↗

PubMed2002

Empathy: Its ultimate and proximate bases.

There is disagreement in the literature about the exact nature of the phenomenon of empathy. There are emotional, cognitive, and conditioning views, applying in varying degrees across species. An adequate description of the ultimate and proximate mechanism can integrate these views. Proximately, the perception of an object's state activates the subject's corresponding representations, which in turn activate somatic and autonomic responses. This mechanism supports basic behaviors (e.g., alarm, social facilitation, vicariousness of emotions, mother-infant responsiveness, and the modeling of competitors and predators) that are crucial for the reproductive success of animals living in groups. The Perception-Action Model (PAM), together with an understanding of how representations change with experience, can explain the major empirical effects in the literature (similarity, familiarity, past experience, explicit teaching, and salience). It can also predict a variety of empathy disorders. The interaction between the PAM and prefrontal functioning can also explain different levels of empathy across species and age groups. This view can advance our evolutionary understanding of empathy beyond inclusive fitness and reciprocal altruism and can explain different levels of empathy across individuals, species, stages of development, and situations.

Adult↗

PubMed2004

Effects of somatic cell count and stage of lactation on the plasmin activity and cheese-making properties of ewe milk.

The experiment was conducted from March to July 2002 using 5 intensively managed flocks of Southern Italy. In each flock, 2 groups of 50 ewes were created. The groups were designated LSCC (low somatic cell count [SCC]) when their milk SCC was lower than 500,000/mL and HSCC (high SCC) when their milk SCC was higher than 1,000,000/mL. Bulk milk and whey samples were analyzed for fat, total protein, lactose, casein, and whey protein contents. Renneting properties of milk were also determined. Moisture, NaCl, and nitrogen fractions were determined in fresh cheese curds. In addition, plasmin (PL) and plasminogen (PG) activities in milk and cheese were monitored. The proteolytic activity of plasmin by urea-polyacrylamide gel electrophoresis and the white blood cell (WBC) differentials were determined. The HSCC resulted in higher pH values in milk and in higher moisture and lower fat contents in fresh cheese curds. Moreover, a lower recovery of fat and whey proteins was obtained from the HSCC than from the LSCC raw milk. The crude protein and casein contents were higher in the HSCC than in the LSCC curds during early and midlactation; an opposite trend was observed in late lactation. Plasmin and PG activities underwent more marked fluctuations in the LSCC than in the HSCC curds through lactation. The results of this experiment demonstrate that the PL activity in ewe milk is markedly influenced by the SCC, although SCC is not the only parameter for predicting PL and PG evolution in ewe milk. The LSCC milk resulted in a higher proteolytic potential of Canestrato pugliese cheese curds.

Animals↗

PubMed2000

Molecular cytogenetic resources for chromosome 4 and comparative analysis of phylogenetic chromosome IV in great apes.

We have generated a panel of 55 somatic cell hybrids retaining fragments of human chromosome 4. Each hybrid has been characterized cytogenetically by FISH and molecularly by 37 STSs, evenly spaced along the chromosome. The panel can be exploited to map subregionally DNA sequences on chromosome 4 and to generate partial chromosome paints useful in the characterization of chromosomal rearrangements involving this chromosome. Furthermore, a panel of 84 YACs mapping on chromosome 4 has been characterized by FISH. A subset of this panel is recognized by STSs used in the somatic cell hybrid characterization. In this way a correlation between the genetic and the physical maps can be established. These resources have been used to investigate the conservation of the phylogenetic chromosome IV in great apes. The results indicate that all the pericentric inversions that differentiate chromosome IV in these species are distinct and that one of the breakpoints frequently lies very close to the centromere. In 4 instances, the YAC containing the breakpoint was identified. The breakpoint in IVq of PTR and MMU lies in the same YAC, suggesting that this breakpoint has been utilized twice in the evolutionary history of this chromosome.

Animals↗

PubMed2002

Genomic plasticity, energy allocations, and the extended longevity phenotypes of Drosophila.

The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal- and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H(2)O(2) from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochondrial and antioxidant changes are likely universal in the Type 1 extended longevity phenotype.

Aging↗

PubMed1998

[Plato's conceptions of disorders of the soul (Ta peri psuchên nosêmata). Timaeus as the beginning of a dynamic and ethic psychopathology].

This contribution to the study of the evolution of fundamental concepts in psychiatry, and in particular of the interpretative models of mental disease, focuses on Plato's conceptions concerning the "disorders of the soul". Plato's "psychopathological" work suggests the decline of an hereditary conglomeration of interpretative arrangements of the irrational phenomena related to mental disease which, corresponding to the social needs of that time, had been united by the belief in myth and its therapeutic value. These archaic religious conceptions have most certainly been reversed by Plato, especially in his Timaeus, one of the three most influential of his dialogues. In a notable passage in this cosmological dialogue (86b ff.) Plato treats of those diseases of the soul which are caused by things physical, whether this be a "defective bodily constitution" or "faulty education". The diseases of the soul are thus no longer considered having a divine origin. Mental diseases to which man is unwittingly subject by defects in birth or education concern himself and his inner life and they cannot be dismissed with simplistic allegories. According to Plato they originate from a conflict, supported by a secret, hidden, irrational "self" that has its roots in the sôma, the rational "self" being only able to recuperate its total integrity if it manages, through self-discipline and knowledge, to check the somatic impulses, the folly of the body. Also, Plato offers a series of remedies to correct the undue influence of body on soul and soul on body, with a view to instituting a right balance and proportion between them. This, together with a stress on "care of the soul", particularly of the divine and immortal element, implicitly assumes that it is in man's power to apply the necessary remedies to himself and effect some sort of readjustment.

Ethics, Medical↗

PubMed1996

Characterization of a novel human dynein-related gene that is specifically expressed in testis.

A novel dynein-related transcript (designated DNEL1) from human adult testis has been identified that can encode a protein with a size of 91087 Da. The complete nucleotide sequence of the open reading frame is the first to be described for a human dynein-related gene. Northern blot analysis of mRNA from 16 different tissues has shown that DNEL1 is expressed specifically in testis. Analysis of somatic cell hybrids has mapped DNEL1 to Chromosome (Chr) 17. Analysis of a panel of 129 whole genome radiaton hybrid clones including 17q22-q25.3 has placed DNEL1 in 17q distal to the ERBA2L locus. DNEL1 shares a high degree of sequence identity and amino acid similarity with the C-terminal region of the outer arm axonemal dynein beta-heavy chains derived from sea urchin and other species, but not to any gene encoding dynein intermediate or light chains described to date. The close similarity of DNEL1 to the C-terminal part of the axonemal beta-heavy chain may suggest an origin from a common progenitor gene and the testis-specific pattern of expression a possible role in sperm development or motility.

Adult↗

PubMed1997

Physical and linkage mapping of the bovine bone morphogenetic protein 1 on the evolutionary break region of BTA 8.

Bone morphogenetic protein 1 (BMP1) has been proposed as a regulatory molecule involved in the binding or activation of other BMP molecules. It has been described as being identical to the enzyme C-proteinase that processes procollagens to fibrillar collagens. A fragment containing an exon of the bovine BMP1 gene was amplified from an adapter-ligated genomic DNA library. The isolated bovine BMP1 fragment was assigned by fluorescence in situ hybridization (FISH) to bovine (BTA) chromosome 8q21, a region containing an evolutionary breakpoint between homology to human (HSA) chromosomes 8 and 9. The assignment to BTA 8 was confirmed by using a hybrid somatic cell panel. The 3' intron region of the amplified genomic BMP1 fragment showed a SSCP polymorphism, and linkage analysis in the International Bovine Reference Panel (IBRP) of families confirmed the boundary position of this gene. The BMP1 gene presents total linkage (theta = 0.00, Z = 3.61) with the lipoprotein lipase gene on BTA 8 and HSA 8 and a larger recombination fraction (theta = 0.11, Z = 5.03) with the marker GGTB2 on BTA 8 and HSA 9. Physical and genetic mapping of the bovine BMP1 gene contribute to narrow the boundary between the HSA 8 and HSA 9 homology segments on BTA 8 and to the comparative mapping between BTA 8, murine chromosome MMU 14, and HSA 8.

Animals↗

PubMed1997

Adaptation and information in ontogenesis and phylogenesis. Increase of complexity and efficiency.

Adaptations during phylogenesis or ontogenesis can occur either by maintaining constant or by increasing the informational content of the organism. In the former case the increasing adaptations to external perturbation are achieved by increasing the rate of genome replication; the increased amount of DNA reflects an increase of total but not of law informational content. In the latter case the adaptations are achieved by either istructionist or evolutionary mechanism or a combination of both. Evolutionary adaptations occur during ontogenesis mainly in the brain-mind, immunological and receptor systems and involve a repertoire of receptors that are., clonally distributed, genome-conditioned and amplified by somatic mutation. Specificity and intensity of responses are achieved a posteriori as a result of natural selection of the clones. The major adaptations during phylogenesis are accompanied by increased complexity. They have been attributed to shifts, short in time and space, against the entropic drive and thus occur notwithstanding the entropic drive and the second law of thermodynamics. The alternative view, is that the generation of complexity is due to the second law of thermodynamics in its extended formulation which includes Prigogine's theorem of minimum entropy production. This view requires however that natural selection provides the biological system with structures that bring the reactions within Onsager's range. The hierarchical organization of the natural world thus reflects a stratified thermodynamic stability. As the evolutionary adaptations generate new information they may be assimilated to Maxwell demon type of processes.

Adaptation, Biological↗

PubMed2004

High-resolution comparative mapping between human chromosomes 4 and 8 and bovine chromosome 27 provides genes and segments serving as positional candidates for udder health in cattle.

To get more information about the order of genes located in Bos taurus (BTA) chromosome 27 segments, supposed to harbor loci influencing clinical mastitis and somatic cell count, and to identify genes that serve as positional candidates for the mentioned traits, we constructed a high-resolution, comparative, and comprehensive gene map for BTA27. The map includes 57 loci in a 5000-rad cattle-hamster whole genome radiation hybrid panel supported by 50 syntenic assignments in a cattle-murine somatic hybrid cell panel. Thirty-eight new loci (36 genes, 2 microsatellites) together with repeated mappings of 5 genes and 7 microsatellites and integration of existing data from 7 microsatellites were used to generate a comprehensive RH5000 map. The RH map, constructed at lod score criterion 8 using the software RHMAP v.3.0, consisted of three linkage groups 23, 22, and 590 cR5000 in length. Gene assignments on BTA27 and the localization of 8 more genes on BTA8 and BTA14 previously predicted on BTA8/BTA27 and BTA14/BTA27 narrowed down significantly the chromosome break points between the three cattle chromosomes and segments on Homo sapiens chromosomes HSA4 and HSA8. Defined evolutionary break points increase the accuracy of comparative in silico mapping of further human genes in conserved chromosome segments of BTA27.

Animals↗

PubMed1990

Allorecognition histocompatibility in a protochordate species: is the relationship to MHC somatic or structural?

Colonial tunicates are complex marine invertebrates (in fact protochordates) that undergo a variety of histocompatibility reactions in their intraspecific competition for feeding surfaces. By means of these reactions colonies fuse with kin, extend domination over a feeding surface, while isolating unrelated conspecifics. The primary determinant of fusion (with kin) or rejection (of non-kin) is a single, highly polymorphic, histocompatibility gene locus (or haplotype), called Fu/HC. Following fusion with nonidentical kin sharing 1 or more Fu/HC allele(s), the fused pair expands both chimeric partners via an asexual budding process, further extending domination over a feeding surface. However, at some later time point an intense set of histoincompatibility reactions occurs between fused kin, resulting in the destruction of all individuals of one of the genotypes, ending the chimeric state. In this review we describe what is known of the genetics and several biological properties encoded by the Fu/HC, and the several independent gene loci that control the colony resorption phenomena that return the colony to the province of a single genotypic individual.

Animals↗

PubMed1997

Insulin-like growth factor binding protein-1: recent findings and new directions.

In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first characterized member of a group of structurally related soluble proteins which specifically bind and modulate the actions of the IGFs. Since then, a wealth of information has accumulated regarding the physiology of this dynamic serum protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp Biol Med 204:4-29) of the status of IGFBP-1 research. The IGFBP-1 protein sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of the cysteine-rich regions are required for optimal IGF binding. The nonconserved IGFBP-1 midregion may act as both a hinge which defines ligand binding characteristics and as a specific target for protease activity. Integrin-binding and phosphorylation sites within the IGFBP-1 sequence have functional significance in vitro, but their physiologic relevance in vivo have not been defined. The human IGFBP-1 and IGFBP-3 genes are contiguous and located in close proximity to the homeobox A (HOXA) gene cluster on chromosome 7. The other IGFBP genes, located on chromosomes 2, 12, and 17, are also associated with HOX clusters, suggesting evolutionary linkage of the IGFBP and HOX gene families. Similarities between the hIGFBP-1 and phosphoenolpyruvate kinase (PEPCK) promoters, including regions conferring insulin, glucocorticoid, and cyclic adenosine-monophosphate responses, are consistent with our previous hypothesis that IGFBP-1 is involved in regulation of glucose metabolism. The tissue-specific patterns of IGFBP-1 gene expression in liver, kidney, decidua, and ovary may be due to stimulation of IGFBP-1 transcription by hepatic nuclear factor 1 (HNF1) proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by several recently developed assay methods. Numerous investigations have confirmed that insulin, via inhibition of IGFBP-1 transcription, is the primary determinant of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II also have specific inhibitory effects on IGFBP-1 expression. Glucocorticoids and cAMP stimulate IGFBP-1 transcription, but these effects are observed only in conditions of low or absent insulin effect. Other stimulants of IGFBP-1 expression include thyroid hormones and epidermal growth factor. Phorbol ester stimulation of IGFBP-1 expression can supersede the effects of insulin in vitro;however, the mechanism and in vivo correlates of this effect have not been determined. Cytokines and, perhaps, growth hormones may affect IGFBP-1 expression, perhaps by altering the regulatory actions of insulin; this effect may have important clinical relevance. IGFBP-1 expression is upregulated in liver and (nonhuman) kidney during postinjury regeneration. The IGF-inhibitory actions of IGFBP-1 has been confirmed by numerous in vitro studies and several in vivo animal investigations, including administration of recombinant IGFBP-1 and IGFBP-1 transgenic models. IGFBP-1 has been shown to inhibit somatic linear growth, weight gain, tissue growth, and glucose metabolism. Moreover, IGFBP-1 appears to be a primary determinant of free IGF-I levels in serum. Excess levels of IGFBP-1 may contribute to growth failure in intrauterine growth restriction and in pediatric chronic renal failure, while low IGFBP-1 levels are associated with obesity and with cardiovascular risk factors in insulin resistance syndromes. Serum IGFBP-1 measurements may be useful biochemical marker in these pathologic conditions. IGFBP-1 is expressed in decidualized stromal cells of the uterine endometrium and in ovarian granulosa cells. IGFBP-1, together with IGFs, insulin, ovarian steroids, cytokines, and other factors, is involved in a complex system which regulates menstrual cycles, ovulation, decidualization, blastocyst implantation, and fetal growth. (ABSTRACT TRUNCATED)

Amino Acid Sequence↗

PubMed1975

Purkinje cell dendritic alterations after transient developmental injury of theexternal granular layer.

To examine the influence of granule cell axons on morphogenesis of their major synaptic target, the Purkinje cell dendrites, a transient injury of the external granular layer of developing rat cerebellum was induced by injecting 10 mg/kg methylazoxymethanol acetate on postnatal days 1, 2, 3 and 4. The antiproliferative action of the drug resulted in a diminution of the mitotic population which slowed the expansion of the internal granular and molecular layers. This was followed by a reconstitution of a thicker than normal external granular layer and a late phase of extensive growth. Perturbations of Purkinje cell dendritic morphology induced by this altered timing of granule cell accumulation were studied with Golgi-Cox impregnation techniques. Systematic observation were made of a number of defined abnormalities of Purkinje cells which included somas positioned below the normal monolayer; elongated dendrites; multiple somatic dendrites; S-shaped dendrites; dendrites disoriented away from the radial direction; and portions of dendrites below the soma of origin. The results indicated that most of these 'abnormalities' occur to a small extent in normal cerebellum but that these experimental conditions induced a bias in favor of their appearance. Some dendritic abnormalities, i.e., dendrites tilted out of the sagittal plane, dendrites directed toward the white matter, and apical dendrites growing vertically between cells of the external granular layer, were not noted in normal cerebellum and we attribute these particular changes to unique developmental possibilities occuring only after a more or less severe injury. This analysis of bias in dendritic morphology subsequent to subtle developmental injury provides informat on on processes of normal development and on the genesis of phylogenetic variants of Purkinje cell morphology.

Abnormalities, Drug-Induced↗

PubMed1995

Scrambling of the actin I gene in two Oxytricha species.

The DNA in a germ-line nucleus (a micronucleus) undergoes extensive processing when it develops into a somatic nucleus (a macronucleus) after cell mating in hypotrichous ciliates. Processing includes destruction of a large amount of spacer DNA between genes and excision of gene-sized molecules from chromosomes. Before processing, micronuclear genes are interrupted by numerous noncoding segments called internal eliminated sequences (IESs). The IESs are excised and destroyed, and the retained macro-nuclear-destined sequences (MDSs) are spliced. MDSs in some micronuclear genes are not in proper order and must be reordered during processing to create functional gene-sized molecules for the macronucleus. Here we report that the micronuclear actin I gene in Oxytricha trifallax WR consists of 10 MDSs and 9 IESs compared to the previously reported 9 MDSs and 8 IESs in the micronuclear actin I gene of Oxytricha nova. The MDSs in the actin I gene are scrambled in a similar pattern in the two species, but the positions of MDS-IES junctions are shifted by up to 14 bp for scrambled and 138 bp for the nonscrambled MDSs. The shifts in MDS-IES junctions create differences in the repeat sequences that are believed to guide MDS splicing. Also, the sizes and sequences of IESs in the micronuclear actin I genes are different in the two Oxytricha species. These observations give insight about the possible origins of IES insertion and MDS scrambling in evolution and show the extraordinary malleability of the germ-line DNA in hypotrichs.

Actins↗

PubMed1991

Evolutionary and biological foundations of malignant tumors.

A hypothesis on evolutionary and biological foundations of malignant tumors is developed. It is suggested that malignant transformation is an inevitable facet of the process of senescence, consequent on the accumulation of somatic mutations. The rate of mutation accumulation is determined by an interplay of internal damage to DNA due to metabolic production of oxidative radicals, and effectiveness of DNA-repair mechanisms. The extent of production of oxidative radicals depends on the metabolism intensity which is determined genetically, and is related to the timing of sexual maturation. The timing of sexual maturation depends on the hazard to life of species members--in species exposed to more dangers, reproduction must be set to occur earlier, at the price of having less effective DNA-repair mechanisms. Target genes for malignant transformation are cellular oncogenes. The deaths due to malignant tumors may thus be considered 'one of the mechanisms of death due to aging'. Environmental carcinogens will only modify the incidence of a small fraction of certain tumor types, as other environmental factors modify the death incidence from other causes.

Biological Evolution↗

PubMed2001

Widespread distribution of extensive chromosomal fragmentation in ciliates.

Ciliates are a diverse group of eukaryotes characterized by their division of nuclear function into a "germ line" micronucleus and a "somatic" macronucleus. After conjugation, chromosomes in the transcriptionally active macronucleus develop by fragmentation, elimination, and amplification of germ line chromosomes. Extensive chromosomal processing that generates a macronucleus with gene-sized fragments has thus far been well documented in members of only one class of ciliates, the Spirotrichea. Here we establish the broad distribution of extensive fragmentation among members of the class Phyllopharyngea and the genera Metopus (order Armophorida) and Nyctotherus (order Clevelandellida). Moreover, analyses of small-subunit rDNA genealogies indicate that gene-sized chromosomes occur in members of the three separate clades: (1) the class Spirotrichea, (2) the class Phyllopharyngea, and (3) the two orders Clevelandellida and Armophorida. Together, these data indicate that the generation of gene-sized chromosomes is widespread and demonstrate multiple origins of extensive fragmentation within ciliates.

Animals↗