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At least 793 records · Page 44Linked to original sources
PubMed1998

Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression.

To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16INK4a gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients. The most frequent genetic alteration during metastatic progression detected was the loss of p16INK4a protein expression (four of 14 cases), whereas no somatic p16INK4a gene mutations were found in any primary or metastatic tumors. LOH analyses showed that most of the chromosome losses including 6q, 8p, 9p, 9q, and 18q were shared between primary tumors and their metastases. Nevertheless, LOH of 6q and 11q and LOH of 7q not detected in primary tumors were, respectively, observed in two lymph node metastases. These results suggest that loss of p16INK4a protein expression (but not p16INK4a gene mutation) and the losses of chromosome arms 6q, 7q, and 11q play an important role in the acquisition of metastatic potential in sporadic melanoma. Furthermore, comparison of genetic profiles between the primary tumor and its metastasis revealed in several cases that heterogenous tumor cell populations might already exist at the early stage of tumorigenesis and evolve independently in the primary tumor and its metastasis, strongly suggesting that metastatic progression of sporadic melanoma is not accounted for by a linear progression model.

Adult↗
PubMed1976

Analysis of mouse oogenesis in vitro. Oocyte isolation and the utilization of exogenous energy sources by growing oocytes.

A method is described for the dissociation of mouse ovaries and the isolation of oocytes free of somatic cells by agitating pieces of ovary in collagenase and deoxyribonuclease in a calcium and magnesium free salt solution. This method yielded about 50% of the growing oocytes from immature mice. The utilization of exogenously administered 14C-labelled energy sources by oocytes in various growth stages was determined by measurement of evolved 14CO2. Little or no evolution of 14CO2 was detected from oocytes of any size incubated in 14C-glucose, lactate or succinate. The production of 14CO2 from 14C-pyruvate increased logarithmically when plotted against increasing oocyte volume with a plateau occurring after occytes reached a volume of 65,500 mum3 (50 mum diameter). Thus, the pattern of energy metabolism for oocyte maturation and early egg cleavage, wherein glucose and lactate are not utilized as efficiently as pyruvate, has been established by the earliest stages of oocyte growth.

Animals↗
PubMed1996

Three abundant germ line-specific transcripts in Volvox carteri encode photosynthetic proteins.

Volvox carteri is a multicellular eukaryotic green alga composed of about 2000 cells of only two differentiated types: somatic and germ line. To understand how embryonic cells are assigned either to somatic or germ line fates, we are investigating the regulation of transcripts that are abundant in only one cell type. Here we report the identity of three transcripts that are coordinately expressed at high levels in germ line cells but not in somatic cells. Surprisingly, all three transcripts encode photosynthetic chloroplast proteins (light-harvesting complex protein, oxygen-evolving enhancer protein 3, and ferredoxin-NADP+ reductase) that are transcribed from nuclear genes. We discuss why these mRNAs might be required at high levels in germ line cells and present a hypothesis, suggested by our results, on the evolution of cell specialization in the Volvocales.

Algal Proteins↗
PubMed1997

Histones: genetic diversity and tissue-specific gene expression.

Histones are the major protein constituents of the chromatin of eukaryotic cell nuclei. This group of basic proteins is extremely conserved throughout evolution and includes five classes termed H1, H2A, H2B, H3 and H4. In mammals, each of these classes except H4 is subdivided into several subtypes. The most divergent class of histones is the H1 protein family, which consists of seven different subtypes, termed H1.1-H1.5, H1 degree, and H1t. The subtypes H1.2 and H1.4 are found in most somatic cell nuclei, whereas H1 degree is found in several differentiated tissues, and H1t is restricted to mammalian testicular cells. Similarly, core histone subtypes replacing the major forms of H2A, H2B or H3 have been described. Biochemical analysis of protein and RNA from different tissues and cell lines demonstrates varied patterns of expression of individual histone subtype genes. Moreover, antibodies against specific histone subtypes and in situ hybridization with subtype-specific probes indicate that the expression of histone subtype genes is in several cases modulated in a tissue-specific manner. This is particularly evident at the different stages of spermatogenesis when chromatin undergoes substantial reorganization, which finally results in the highly condensed state of chromatin of the mature sperm head.

Animals↗
PubMed2004

Differentiation capacity of epithelial cells in the sponge Suberites domuncula.

Sponges (phylum Porifera) represent the oldest metazoans. Their characteristic metazoan adhesion molecules and transcription factors enable them to establish a complex "Bauplan"; three major differentiated cell types (epithelial cells, skeletal cells/sclerocytes, and contractile cells) can be distinguished. Since no molecular markers are as yet available to distinguish these somatic cells or the corresponding embryonic cells from which they originate, we have selected the following three genes for their characterization: noggin (a signaling molecule in development), a caspase that encodes an apoptotic molecule, and silicatein. Silicatein is an enzyme that is involved in the synthesis of siliceous spicules and can hence be considered as a marker for scleroblasts. We have used the demosponge Suberites domuncula as a model system. During the hatching of the gemmules (asexual reproduction bodies) of S. domuncula, the expression of both noggin and caspase increases, whereas no transcripts for silicatein can be detected, irrespective of the presence of silicate or ferric iron (Fe3+) in the medium. In contrast, in adult specimens, silicate/Fe3+ cause an increased expression of these genes. In situ analysis has revealed that the first cells that express noggin, caspase, and silicatein lie in the epithelial layer of the pinacoderm. In a later phase, the noggin- and silicatein-positive cells migrate into the mesohyl, where they are found in association with spicules. Thus, the pinacoderm of sponges contains cells that have a differentiating capacity and from which somatic cells, such as skeletal cells/sclerocytes, derive.

Amino Acid Sequence↗
PubMed1998

Male reproductive strategy and decreased longevity.

An explanation of the inter-gender difference in longevity consistent with the 'disposable soma' theory of ageing is proposed. It is based on the concept of r-K selection as applied to the inter-gender situation. The concept predicts that the gender with a higher potential reproductive rate (males) should invest relatively less in somatic maintenance, which in its turn should result in a lower longevity according to the 'disposable soma' theory of ageing. In females, which are interpreted as K-selected organisms, the reproductive strategy strongly depends on steady, secure constitution designed for oocyte/embryo bearing and is therefore closely related to somatic maintenance, whereas in (r-selected) males it has a greater behavioural component--risky, variable, with a greater potential productive success at the expense of somatic maintenance. The higher metabolic and growth rates, a higher premature mortality and a longer period of sexual competence of males also find explanation as a complex of r-selected traits.

Aging↗
PubMed1995

Functional haplodiploidy: a mechanism for the spread of insecticide resistance in an important international insect pest.

The coffee berry borer, Hypothenemus hampei, is the most important insect pest of coffee worldwide and has an unusual life history that ensures a high degree of inbreeding. Individual females lay a predominantly female brood within individual coffee berries and because males are flightless there is almost entirely full sib mating. We investigated the genetics associated with this interesting life history after the important discovery of resistance to the cyclodiene type insecticide endosulfan. Both the inheritance of the resistance phenotype and the resistance-associated point mutation in the gamma-aminobutyric acid receptor gene Rdl were examined. Consistent with haplodiploidy, males failed to express and transmit paternally derived resistance alleles. Furthermore, while cytological examination revealed that males are diploid, one set of chromosomes was condensed, and probably nonfunctional, in the somatic cells of all males examined. Moreover, although two sets of chromosomes were present in primary spermatocytes, the chromosomes failed to pair before the single meiotic division, and only one set was packaged in sperm. Thus, the coffee berry borer is "functionally" haplodiploid. Its genetics and life history may therefore represent an interesting intermediate step in the evolution of true haplodiploidy. The influence of this breeding system on the spread of insecticide resistance is discussed.

Alleles↗
PubMed1987

Evolutionary and somatic selection of the antibody repertoire in the mouse.

The repertoire of antibody variable (V) regions has been subject to evolutionary selection, affecting both the diversity of V region genes in the germline and their expression in the B lymphocyte population and its subsets. In ontogeny, contact with an antigen leads to the expansion of B cells expressing antibodies complementary to it. In a defined phase of B cell differentiation, new sets of V regions are generated from the existing repertoire through somatic hypermutation. Cells carrying advantageous antibody mutants are selected into the memory compartment and produce a stable secondary response upon reexposure to the antigen.

Animals↗
PubMed1995

[The human genome with special emphasis on chromosome 1].

The development of knowledge of human genomes to the present stage was influenced by three specific genetic methodologies. Chromosomology after the beginning of the fifties, genetics of somatic cells, which began in the mid-sixties and molecular genetics which started at the end of the seventies (1). All methodologies contributed in their time to the mapping of genes and the construction of gene maps. The submitted review is devoted in particular to chromosome 1. Information pertaining to gene mapping helps to elucidate the evolution, organization of controlling mechanisms of the pathogenesis of hereditary disease, neoplasias, malformations for prenatal and premorbid diagnosis and perspectively for gene therapy.

Chromosome Aberrations↗
PubMed1998

[Improved prognosis of functional abdominal complaints by attending to psychic factors].

OBJECTIVE: To determine the assessment by physicians of psychic factors in patients with functional abdominal complaints, and the relationship between the assessment and the evolution of the abdominal complaints. DESIGN: Prospective, descriptive. SETTING: Outpatient Clinic Internal Medicine, University Hospital Nijmegen, the Netherlands. METHODS: 120 patients with functional abdominal complaints were asked to indicate by questionnaires the severity and meaning of their complaints prior to and at the end of the visits to their internist. Internists were asked how they rated the somatic and non-somatic complaint dimensions in their patients. RESULTS: Overall, internists perceived the severity and details of the abdominal complaints correctly. Prognostically unfavourable complaint-related cognitions and emotions were perceived less correctly. During the outpatient consulting period, patients' anxiety and somatic attributions diminished, especially when the internist had perceived these aspects correctly. Six months after the first outpatient visit the abdominal complaints of these reassured patients had improved, compared with patients with persistent somatic attributions; the latter made more frequent use of health care services at follow-up (GP visits, drug use). CONCLUSION: Systematic exploration of somatic and non-somatic complaint dimensions by physicians could be an important tool in improving the prognosis and diminishing the medical consumption in patients with functional abdominal complaints.

Abdominal Pain↗
PubMed2006

A hydrodynamics approach to the evolution of multicellularity: flagellar motility and germ-soma differentiation in volvocalean green algae.

During the unicellular-multicellular transition, there are opportunities and costs associated with larger size. We argue that germ-soma separation evolved to counteract the increasing costs and requirements of larger multicellular colonies. Volvocalean green algae are uniquely suited for studying this transition because they range from unicells to multicellular individuals with germ-soma separation. Because Volvocales need flagellar beating for movement and to avoid sinking, their motility is modeled and analyzed experimentally using standard hydrodynamics. We provide comparative hydrodynamic data of an algal lineage composed of organisms of different sizes and degrees of complexity. In agreement with and extending the insights of Koufopanou, we show that the increase in cell specialization as colony size increases can be explained in terms of increased motility requirements. First, as colony size increases, soma must evolve, the somatic-to-reproductive cell ratio increasing to keep colonies buoyant and motile. Second, increased germ-soma specialization in larger colonies increases motility capabilities because internalization of nonflagellated germ cells decreases colony drag. Third, our analysis yields a limiting maximum size of the volvocalean spheroid that agrees with the sizes of the largest species known. Finally, the different colony designs in Volvocales reflect the trade-offs between reproduction, colony size, and motility.

Biological Evolution↗
PubMed2003

Structural plasticity and the evolution of antibody affinity and specificity.

The germline precursor to the ferrochelatase antibody 7G12 was found to bind the polyether jeffamine in addition to its cognate hapten N-methylmesoporphyrin. A comparison of the X-ray crystal structures of the ligand-free germline Fab and its complex with either hapten or jeffamine reveals that the germline antibody undergoes significant conformational changes upon the binding of these two structurally distinct ligands, which lead to increased antibody-ligand complementarity. The five somatic mutations introduced during affinity maturation lead to enhanced binding affinity for hapten and a loss in affinity for jeffamine. Moreover, a comparison of the crystal structures of the germline and affinity-matured antibodies reveals that somatic mutations not only fix the optimal binding site conformation for the hapten, but also introduce interactions that interfere with the binding of non-hapten molecules. The structural plasticity of this germline antibody and the structural effects of the somatic mutations that result in enhanced affinity and specificity for hapten likely represent general mechanisms used by the immune response, and perhaps primitive proteins, to evolve high affinity, selective receptors for so many distinct chemical structures.

Antibody Affinity↗
PubMed1977

Immune surveillance against virus-induced tumors and nonrejectability of spontaneous tumors: contrasting consequences of host versus tumor evolution.

Spontaneous tumours are defined as tumors that develop in the absence of all experimental interference. In contrast to the widely documented, strong rejection reactions against most virus-induced tumors, spontaneous tumors evoke little or no detectable rejection reaction in intact or preimmunized syngeneic hosts. The difference can be viewed in relation to the contrasting natural history of the two conditions. Spontaneous tumors evolve in several steps, as a fule. "Tumor progression" is a microevolutionary process at the level of the somatic tissue where successive clonal variants replace each other. Each new variant gains the upper hand due to its greater independence of some restricting host mechanism. Independence of immune restrictions must be part of this process. Host selection for immune resistance apparently plays no major role here, presumably because most of the naturally occurring tumors arise after the host has passed the peak of its reproductive period. Protection against the oncogenic effects of ubiquitous tumor viruses is, on the other hand, the result of host selection for immune mechanisms favoring prompt rejection of virus-transformed cells. This is neither synonymous with nor related to protection against the viral infection per se, which is frequently successful and usually quite harmless. A certain relationship can be perceived between the degree of viral ubiquity and the strength of immune protection against the corresponding tumor cells. Natural selection for host recognition of commonly occurring, virally induced changes in neoplastic cell membranes can be surmised to occur, at least in part, by the fixation of appropriate immune responsiveness (Ir) genes. The role of Ir genes for tumor recognition can be approached by the genetic analysis of the F1 hybrid resistance effect. Unresponsiveness to spontaneous tumors may be overcome by target-cell modification, e.g., by chemical coupling, somatic cell hybridization, or viral "xenogenization".

Animals↗
PubMed1993

Molecular evolution of the human immunoglobulin E response: high incidence of shared mutations and clonal relatedness among epsilon VH5 transcripts from three unrelated patients with atopic dermatitis.

We have analyzed the nucleotide sequences of 19 epsilon VH5 transcripts derived from in vivo isotype switched peripheral blood B cells of three patients with atopic dermatitis. Comparison with the patients' own germline VH5 gene segments revealed that the epsilon transcripts were derived from both functional members of the human VH5 gene family and harbored numerous somatic mutations (range 5-36 per VH5 gene). In two patients, we detected clonally related but diverged transcripts, permitting the construction of a genealogical tree in one patient. We observed a high proportion of shared silent (S) and replacement (R) mutations among epsilon VH5 sequences derived from all three individuals, even among transcripts descending from the two different germline VH5 gene segments. A remarkably high number of these mutations is shared with previously reported VH5 genes encoding antibodies with defined specificities. The shared S mutations, and likely a fraction of the R mutations, appear to mark preferential sites ("hot spots") of somatic hypermutations in human VH5 genes. The distribution of R and S mutations over complementarity determining region and framework regions in the majority of VH regions deviated from that characteristic of antigen-driven immune response. We hypothesize that the V regions of immunoglobulin E-bearing B cells have accumulated "selectively neutral" mutations over extended periods of clonal expansion, resulting in unusual R/S ratios. We propose that the molecular characteristics of the epsilon VH regions in atopic dermatitis may be representative of antigens that recurrently or chronically stimulate the immune system.

Adult↗
PubMed2004

The shortest telomeres drive karyotype evolution in transformed cells.

Maintenance of telomeres is essential for chromosome stability. In the absence of telomerase, telomeres shorten with cell division until they approach a stability threshold, at which point cells enter senescence. When senescence-signaling pathways are inactive, further telomere shortening leads to chromosome instability characterized by telomeric fusions and breakage-fusion-bridge (BFB) cycles. Since the distribution of telomere lengths among chromosome extremities is heterogeneous, we wondered about the impact of such variability on the stability of particular chromosome arms. We correlated the initial length of individual telomeres in telomerase-negative-transformed cells with the stability of the corresponding chromosome arms during the precrisis period. We show that arms carrying the shortest telomeres are the first to become unstable and this instability affects the chromosome homologues with shorter telomeres almost exclusively. The analysis of several postcrisis cell populations, which had stabilized their telomeres by re-expressing telomerase, showed that the karyotypic outcome is strongly influenced by the initial telomere length heterogeneity. The timing of telomerase re-expression also seems to play a role in limiting the extent of karyotypic changes, probably by reducing the frequency of telomeric fusions and hence BFB. Since the distribution of telomere lengths within somatic cells is proper to every individual, our results predict that the risk for a particular chromosome arm of becoming unstable early in tumorigenesis will differ between individuals and contribute directly to the heterogeneity of chromosome aberrations found in tumors.

Cell Division↗
PubMed1999

Signals from the reproductive system regulate the lifespan of C. elegans.

Understanding how the ageing process is regulated is a fascinating and fundamental problem in biology. Here we demonstrate that signals from the reproductive system influence the lifespan of the nematode Caenorhabditis elegans. If the cells that give rise to the germ line are killed with a laser microbeam, the lifespan of the animal is extended. Our findings suggest that germline signals act by modulating the activity of an insulin/IGF-1 (insulin-like growth factor) pathway that is known to regulate the ageing of this organism. Mutants with reduced activity of the insulin/IGF-1-receptor homologue DAF-2 have been shown to live twice as long as normal, and their longevity requires the activity of DAF- 16, a member of the forkhead/winged-helix family of transcriptional regulators. We find that, in order for germline ablation to extend lifespan, DAF-16 is required, as well as a putative nuclear hormone receptor, DAF-12. In addition, our findings suggest that signals from the somatic gonad also influence ageing, and that this effect requires DAF-2 activity. Together, our findings imply that the C. elegans insulin/IGF-1 system integrates multiple signals to define the animal's rate of ageing. This study demonstrates an inherent relationship between the reproductive state of this animal and its lifespan, and may have implications for the co-evolution of reproductive capability and longevity.

Aging↗
PubMed1998

Immunological origins of binding and catalysis in a Diels-Alderase antibody.

The three-dimensional structure of an antibody (39-A11) that catalyzes a Diels-Alder reaction has been determined. The structure suggests that the antibody catalyzes this pericyclic reaction through a combination of packing and hydrogen-bonding interactions that control the relative geometries of the bound substrates and electronic distribution in the dienophile. A single somatic mutation, serine-91 of the light chain to valine, is largely responsible for the increase in affinity and catalytic activity of the affinity-matured antibody. Structural and functional studies of the germ-line precursor suggest that 39-A11 and related antibodies derive from a family of germ-line genes that have been selected throughout evolution for the ability of the encoded proteins to form a polyspecific combining site. Germ line-encoded antibodies of this type, which can rapidly evolve into high-affinity receptors for a broad range of structures, may help to expand the binding potential associated with the structural diversity of the primary antibody repertoire.

Amino Acid Sequence↗
PubMed2006

A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation.

Class switch DNA recombination (CSR) and somatic hypermutation (SHM) are central to the maturation of the Ab response. Both processes involve DNA mismatch repair (MMR). MMR proteins are recruited to dU:dG mispairs generated by activation-induced cytidine deaminase-mediated deamination of dC residues, thereby promoting S-S region synapses and introduction of mismatches (mutations). The MutL homolog Mlh3 is the last complement of the mammalian set of MMR proteins. It is highly conserved in evolution and is essential to meiosis and microsatellite stability. We used the recently generated knockout mlh3(-/-) mice to address the role of Mlh3 in CSR and SHM. We found that Mlh3 deficiency alters both CSR and SHM. mlh3(-/-) B cells switched in vitro to IgG and IgA but displayed preferential targeting of the RGYW/WRCY (R = A or G, Y = C or T, W = A or T) motif by Sgamma1 and Sgamma3 breakpoints and introduced more insertions and fewer donor/acceptor microhomologies in Smu-Sgamma1 and Smu-Sgamma3 DNA junctions, as compared with mlh3(+/+) B cells. mlh3(-/-) mice showed only a slight decrease in the frequency of mutations in the intronic DNA downstream of the rearranged J(H)4 gene. However, the residual mutations were altered in spectrum. They comprised a decreased proportion of mutations at dA/dT and showed preferential RGYW/WRCY targeting by mutations at dC/dG. Thus, the MMR Mlh3 protein plays a role in both CSR and SHM.

Animals↗