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PubMed2003

Fugu rubripes possesses genes for the entire set of the ITAM-bearing transmembrane signal subunits.

The transmembrane signaling subunits (TSSs) bearing the immunoreceptor tyrosine-based activation motif (ITAM) play a crucial role in triggering the effector functions of mammalian leukocytes. The involvement in key immune reactions and obvious extension through duplication events make TSSs valuable markers of the evolution of the immune system. We surveyed the genomic sequences of the teleostean fish Fugu rubripes for the presence of genes encoding these accessory molecules. Automatic gene prediction was not efficient because of the poor ability of the programs used to recognize the short exons encoding the intracellular regions of TSSs. However, the unique compactness of the Fugu genome and the conservation of the exon/intron arrangements of the TSS genes facilitated their recognition by visual inspection of the candidate genomic sequences. Evidence for the presence of the CD3epsilon, CD3gamma/delta, CD79a, CD79b, TCRzeta, FcRgamma, DAP12 and DAP10 genes in the Fugu genome was obtained. Furthermore, conserved synteny for the short regions including the TSS genes was revealed by comparison of the Fugu and human genomes. The data demonstrate that the set of TSSs arose before the teleost-tetrapod split and provide a starting point for experimental investigation of the molecular evolution of the leukocyte-activating receptor complexes from fish species to mammals.

Amino Acid Sequence↗

PubMed1991

Koch's postulates and experimental atherosclerosis.

Koch's postulates contributed substantially to the evolution of scientific knowledge of infectious diseases, but are inapplicable to chronic non-infectious, degenerative diseases such as atherosclerosis. In experimental atherogenesis compliance with appropriately modified postulates is essential to preclude spurious causes from consideration. The crux of such postulates is that the experimental procedure must reproduce the disease and its complications and their pathogenesis and experimental conditions must be analogous to those prevailing in man. Since atherosclerosis is not species specific to man and consists of multiple lesions, which develop independently of one another but can ultimately coalesce, reproduction of the disease in a localized segment of a blood vessel in susceptible animals under conditions similar to those prevailing in man would comply with the spirit of Koch's postulates.

Animals↗

PubMed1998

Molecular ecology and evolution of Streptococcus thermophilus bacteriophages--a review.

Bacteriophages attacking Streptococcus thermophilus, a lactic acid bacterium used in milk fermentation, are a threat to the dairy industry. These small isometric-headed phages possess double-stranded DNA genomes of 31 to 45 kb. Yoghurt-derived phages exhibit a limited degree of variability, as defined by restriction pattern and host range, while a large diversity of phage types have been isolated from cheese factories. Despite this diversity all S. thermophilus phages, virulent and temperate, belong to a single DNA homology group. Several mechanisms appear to create genetic variability in this phage group. Site-specific deletions, one type possibly mediated by a viral recombinase/integrase, which transformed a temperate into a virulent phage, were observed. Recombination as a result of superinfection of a lysogenic host has been reported. Comparative DNA sequencing identified up to 10% sequence diversity due to point mutations. Genome sequencing of the prototype temperate phage phi Sfi21 revealed many predicted proteins which showed homology with phages from Lactococcus lactis suggesting horizontal gene transfer. Homology with phages from evolutionary unrelated bacteria like E. coli (e.g. lambdoid phage 434 and P1) and Mycobacterium phi L5 was also found. Due to their industrial importance, the existence of large phage collections, and the whole phage genome sequencing projects which are currently underway, the S. thermophilus phages may present an interesting experimental system to study bacteriophage evolution.

Bacteriophages↗

PubMed2001

Animal models of fulminant hepatic failure: need to test liver support devices.

Fulminant hepatic failure is one of the most dramatic entities in clinical medicine, but experimental studies of its pathogenesis, evolution and treatment have, so far been limited by the lack of satisfactory animal models for testing new supportive treatment options. The variable aetiology, complex pathogenetic mechanisms and inconstant clinical evolution of human fulminant hepatic failure make it particularly difficult to establish an "ideal fulminant hepatic failure animal model" suitable for all studies: it is no longer mandatory to develop one single model serving all possible scientific needs, but the use of a specific model for a specific issue is more advisable. The currently available animal models of fulminant hepatic failure are the hepatotoxic, surgical and combined hepatotoxic and surgical models. From a general point of view, surgical models may be particularly appropriate for studying the consequences of hepatic necrosis on cerebral oedema. The anhepatic model is very useful for validating new supportive measures to bridge the period between the onset of fulminant hepatic failure and the time at which a suitable organ becomes available and, despite the many difficulties involved in their development, hepatotoxic models may still be useful for mimicking an acetaminophen overdose. The efficacy and reproducibility of a liver support system can be demonstrated by means of preclinical experimental models that mimic the specific application required in humans as closely as possible.

Acetaminophen↗

PubMed2001

Comparison of genetic divergence and fitness between two subclones of Helicobacter pylori.

Helicobacter pylori has a very plastic genome, reflecting its high rate of recombination and point mutation. This plasticity promotes divergence of the population by the development of subclones and presumably enhances adaptation to host niches. We have investigated the genotypic and phenotypic characteristics of two such subclones isolated from one patient as well as the genetic evolution of these isolates during experimental infection. Whole-genome genotyping of the isolates using DNA microarrays revealed that they were more similar to each other than to a panel of other genotyped strains recovered from different hosts. Nonetheless, they still showed significant differences. For example, one isolate (67:21) contained the entire Cag pathogenicity island (PAI), whereas the other (67:20) had excised the PAI. Phenotypic studies disclosed that both isolates expressed adhesins that recognized human histo-blood group Lewis(b) glycan receptors produced by gastric pit and surface mucus cells. In addition, both isolates were able to colonize, to equivalent density and with similar efficiency, germ-free transgenic mice genetically engineered to synthesize Lewis(b) glycans in their pit cells (12 to 14 mice/isolate). Remarkably, the Cag PAI-negative isolate was unable to colonize conventionally raised Lewis(b) transgenic mice harboring a normal gastric microflora, whereas the Cag PAI-positive isolate colonized 74% of the animals (39 to 40 mice/isolate). The genomic evolution of both isolates during the infection of conventionally raised and germ-free mice was monitored over the course of 3 months. The Cag PAI-positive isolate was also surveyed after a 10 month colonization of conventionally raised transgenic animals (n = 9 mice). Microarray analysis of the Cag PAI and sequence analysis of the cagA, recA, and 16S rRNA genes disclosed no changes in recovered isolates. Together, these results reveal that the H. pylori population infecting one individual can undergo significant divergence, creating stable subclones with substantial genotypic and phenotypic differences.

Adhesins, Bacterial↗

PubMed2003

Homeosis and atavistic regeneration: the 'biogenetic law' in Entwicklungsmechanik.

Homeosis is a developmental abnormality corresponding to the transformation of a part of the body into another one. This term was introduced in 1894 by William Bateson, who aimed to make an inventory of all kinds of biological variation in order to understand how evolution proceeds. But, immediately afterwards experimental embryology, or Entwicklungsmechanik in Germany, adopted and redefined this term to refer to abnormal regenerations in which the newly developed organ was not identical to the initial one but rather resembled another part of the body. At that time, many experimental embryologists, such as Wilhelm Roux, were calling for the elimination of any phylogenetic explanation of development and were attempting to promote more mechanistic, proximate explanations. Despite these recommendations, several biologists continued to account for developmental processes by turning to phylogeny instead of mechanical forces. The case of homeosis is representative. Indeed, abnormal regenerations were often seen as examples of atavisms, or recurrence of ancestral characteristics, and many embryologists appealed to Ernst Haeckel's 'fundamental biogenetic law' to explain these strange phenomena. The break between Haeckelian tradition and Entwicklungsmechanik is thus less radical than often assumed, and the homeosis concept represents one of the factors of this continuity.

Biological Evolution↗

PubMed2000

Aneuploidy precedes and segregates with chemical carcinogenesis.

A century ago, Boveri proposed that cancer is caused by aneuploidy, an abnormal balance of chromosomes, because aneuploidy correlates with cancer and because experimental aneuploidy generates "pathological" phenotypes. Half a century later, when cancers were found to be nonclonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result, aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer. However, we have recently proposed a two-stage mechanism of carcinogenesis that resolves the discrepancy between clonal mutation and nonclonal karyotypes. The proposal is as follows: in stage 1, a carcinogen "initiates" carcinogenesis by generating a preneoplastic aneuploidy; in stage 2, aneuploidy causes asymmetric mitosis because it biases balance-sensitive spindle and chromosomal proteins and alters centrosomes both numerically and structurally (in proportion to the degree of aneuploidy). Therefore, the karyotype of an initiated cell evolves autocatalytically, generating ever-new chromosome combinations, including neoplastic ones. Accordingly, the heterogeneous karyotypes of "clonal" cancers are an inevitable consequence of the karyotypic instability of aneuploid cells. The notorious long latent periods, of months to decades, from carcinogen to carcinogenesis, would reflect the low probability of evolving by chance karyotypes that compete favorably with normal cells, in principle analagous to natural evolution. Here, we have confirmed experimentally five predictions of the aneuploidy hypothesis: (1) the carcinogens dimethylbenzanthracene and cytosine arabinoside induced aneuploidy in a fraction of treated Chinese hamster embryo cells; (2) aneuploidy preceded malignant transformation; (3) transformation of carcinogen-treated cells occurred only months after carcinogen treatment, i.e., autocatalytically; (4) preneoplastic aneuploidy segregated with malignant transformation in vitro and with 14 of 14 tumors in animals; and (5) karyotypes of tumors were heterogeneous. We conclude that, with the carcinogens studied, aneuploidy precedes cancer and is necessary for carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Disk-covering, a fast-converging method for phylogenetic tree reconstruction.

The evolutionary history of a set of species is represented by a phylogenetic tree, which is a rooted, leaf-labeled tree, where internal nodes represent ancestral species and the leaves represent modern day species. Accurate (or even boundedly inaccurate) topology reconstructions of large and divergent trees from realistic length sequences have long been considered one of the major challenges in systematic biology. In this paper, we present a simple method, the Disk-Covering Method (DCM), which boosts the performance of base phylogenetic methods under various Markov models of evolution. We analyze the performance of DCM-boosted distance methods under the Jukes-Cantor Markov model of biomolecular sequence evolution, and prove that for almost all trees, polylogarithmic length sequences suffice for complete accuracy with high probability, while polynomial length sequences always suffice. We also provide an experimental study based upon simulating sequence evolution on model trees. This study confirms substantial reductions in error rates at realistic sequence lengths.

Algorithms↗

PubMed2005

Elevated evolutionary rates in the laboratory strain of Saccharomyces cerevisiae.

By using the maximum likelihood method, we made a genome-wide comparison of the evolutionary rates in the lineages leading to the laboratory strain (S288c) and a wild strain (YJM789) of Saccharomyces cerevisiae and found that genes in the laboratory strain tend to evolve faster than in the wild strain. The pattern of elevated evolution suggests that relaxation of selection intensity is the dominant underlying reason, which is consistent with recurrent bottlenecks in the S. cerevisiae laboratory strain population. Supporting this conclusion are the following observations: (i) the increases in nonsynonymous evolutionary rate occur for genes in all functional categories; (ii) most of the synonymous evolutionary rate increases in S288c occur in genes with strong codon usage bias; (iii) genes under stronger negative selection have a larger increase in nonsynonymous evolutionary rate; and (iv) more genes with adaptive evolution were detected in the laboratory strain, but they do not account for the majority of the increased evolution. The present discoveries suggest that experimental and possible industrial manipulations of the laboratory strain of yeast could have had a strong effect on the genetic makeup of this model organism. Furthermore, they imply an evolution of laboratory model organisms away from their wild counterparts, questioning the relevancy of the models especially when extensive laboratory cultivation has occurred. In addition, these results shed light on the evolution of livestock and crop species that have been under human domestication for years.

Biological Evolution↗

PubMedDate not supplied

[Experimental production of bone sarcomas in the rabbit by a single local injection of beryllium].

The local intra-osseous injection of double zinc beryllium silicate into the tibial or femoral epiphysis of a rabbit causes an osteogenic sarcoma in 70 p. 100 of cases. These experimental conditions make it possible to reveal early non specific radiological alterations, later on secondary alterations corresponding to the development of the sarcoma and finally to follow the spontaneous evolution of the tumor. Moreover, this experimental process of induction of an osteogenic sarcoma by means of a local intra-osseous injection is vastly better than an intra-venous injection which causes straight-away multiple visceral lesions.

Animals↗

PubMed1991

Studies of translocation catalysis.

There is a symbiotic relationship between the evolution of fundamental theory and the winning of experimentally-based knowledge. The impact of the General Chemiosmotic Theory on our understanding of the nature of membrane transport processes is described and discussed. The history of experimental studies on transport catalysed by ionophore antibiotics and the membrane proteins of mitochondria and bacteria are used to illustrate the evolution of knowledge and theory. Recent experimental approaches to understanding the lactose-H+ symport protein of Escherichia coli and other sugar porters are described to show that the lack of experimental knowledge of the three-dimensional structures of the proteins currently limits the development of theories about their molecular mechanism of translocation catalysis.

Amino Acid Sequence↗

PubMed1998

Mechanism and evolution of protein dimerization.

We have investigated the mechanism and the evolutionary pathway of protein dimerization through analysis of experimental structures of dimers. We propose that the evolution of dimers may have multiple pathways, including (1) formation of a functional dimer directly without going through an ancestor monomer, (2) formation of a stable monomer as an intermediate followed by mutations of its surface residues, and (3), a domain swapping mechanism, replacing one segment in a monomer by an equivalent segment from an identical chain in the dimer. Some of the dimers which are governed by a domain swapping mechanism may have evolved at an earlier stage of evolution via the second mechanism. Here, we follow the theory that the kinetic pathway reflects the evolutionary pathway. We analyze the structure-kinetics-evolution relationship for a collection of symmetric homodimers classified into three groups: (1) 14 dimers, which were referred to as domain swapping dimers in the literature; (2) nine 2-state dimers, which have no measurable intermediates in equilibrium denaturation; and (3), eight 3-state dimers, which have stable intermediates in equilibrium denaturation. The analysis consists of the following stages: (i) The dimer is divided into two structural units, which have twofold symmetry. Each unit contains a contiguous segment from one polypeptide chain of the dimer, and its complementary contiguous segment from the other chain. (ii) The division is repeated progressively, with different combinations of the two segments in each unit. (iii) The coefficient of compactness is calculated for the units in all divisions. The coefficients obtained for different cuttings of a dimer form a compactness profile. The profile probes the structural organization of the two chains in a dimer and the stability of the monomeric state. We describe the features of the compactness profiles in each of the three dimer groups. The profiles identify the swapping segments in domain swapping dimers, and can usually predict whether a dimer has domain swapping. The kinetics of dimerization indicates that some dimers which have been assigned in the literature as domain swapping cases, dimerize through the 2-state kinetics, rather than through swapping segments of performed monomers. The compactness profiles indicate a wide spectrum in the kinetics of dimerization: dimers having no intermediate stable monomers; dimers having an intermediate with a stable monomer structure; and dimers having an intermediate with a stable structure in part of the monomer. These correspond to the multiple evolutionary pathways for dimer formation. The evolutionary mechanisms proposed here for dimers are applicable to other oligomers as well.

Biological Evolution↗

PubMed1997

Perinatal lethality in H19 enhancers-Igf2 transgenic mice.

The insulin-like growth factor II (IGFII) is a mitogen for a number of cell types in vitro and is required for normal embryonic growth. It has been hypothesized that overexpression of IGF2 is responsible for the increased growth and tumor predisposition in patients with Beckwith-Wiedemann syndrome. Association of increased levels of IGFII with increased growth is also incorporated in a current model for the evolution of Igf2 imprinting. Different experimental approaches to increasing IGFII levels in the mouse have yielded different results with respect to its effects on growth, viability, and tumor development. To investigate the consequences of IGf2 overexpression in the embryonic period, without alterations in the activity of other genes, we produced transgenic mice that express the Igf2 gene under the control of the H19 enhancers. Transgene expression in the embryonic period had no significant effect on the overall size of the embryos, but was associated with perinatal lethality in homozygous, and some heterozygous, mice. A large fraction of homozygous mice also developed a cleft palate. These findings indicate that overexpression of Igf2 can have an adverse effect on viability in the absence of a pronounced effect on overall body growth. The results are consistent with the view that growth and perinatal viability are affected differently by Igf2 overexpression in endodermal and mesodermal tissues.

Animals↗

PubMed1999

Early perfusion after controlled cortical impact in rats: quantification by arterial spin-labeled MRI and the influence of spin-lattice relaxation time heterogeneity.

Early posttraumatic cerebral hypoperfusion is implicated in the evolution of secondary damage after experimental and clinical traumatic brain injury (TBI). This is the first report of cerebral blood flow (CBF) measurement by continuous arterial spin-labeled magnetic resonance imaging (MRI) early after TBI in rats using the controlled cortical impact (CCI) model. CCI reduced CBF globally at approximately 3 hr (versus normal), with 85% and 49% reductions in a contused cortical region and contralateral cortex, respectively. In contrast, a prior MRI study from this laboratory showed at 24 hr post trauma a focal CBF reduction restricted to the injury site. In vivo spin-lattice relaxation time (T(1obs)), which is used in CBF quantification, was spatially heterogeneous early after CCI, a time when edema is developing in injured brain tissue. At 4.7 T, T(1obs) values are increased 29% in the contusion (versus normal), consequently reducing CBF quantification to a similar degree. MRI should facilitate coupling posttraumatic CBF with long-term functional outcome. Magn Reson Med 42:673-681, 1999.

Animals↗

PubMed2002

The beneficial effect of interleukin-12 on arthritis induced by group B streptococci is mediated by interferon-gamma and interleukin-10 production.

OBJECTIVE: To assess the effect of interleukin-12 (IL-12) administration on the evolution of systemic infection and septic arthritis induced by group B streptococci (GBS) in mice. METHODS: CD1 mice were inoculated intravenously with arthritogenic strain 1/82 of type IV GBS. Exogenous murine IL-12 was administered intraperitoneally 18 hours or 5 days after infection with 1 x 10(7) GBS, at doses ranging from 0.5 to 2.5 microg per mouse. Mice were monitored daily for survival and for signs of arthritis. In a subsequent set of experiments, mice were killed at selected times for examination of bacterial clearance, histopathologic changes in the joints, and cytokine production. RESULTS: IL-12 administration before the onset of clinical signs had a beneficial effect on GBS-induced arthritis and was clearly dose-dependent. The 2.5-microg dose per mouse totally prevented death from GBS-induced arthritis. The decrease in pathology was associated with a reduction of the bacterial burden and a change in the cytokine profile. In particular, systemic and joint levels of interferon-gamma (IFN gamma) and IL-10 significantly increased in mice treated with IL-12, whereas a decrease in IL-6 and IL-1 beta production was observed. The beneficial effects of IL-12, in terms of the incidence and severity of articular lesions, were reversed by coadministration of anti-IFN gamma or anti-IL-10-neutralizing antibodies. CONCLUSION: The findings of this study demonstrate that IL-12 is important in controlling the cytokine production that leads to the evolution of GBS-induced experimental arthritis. The amelioration of articular lesions is mostly attributable to IL-12-induced IFN gamma, but with a relevant participation of IL-12-induced IL-10.

Adjuvants, Immunologic↗

PubMed2007

Reaction chemistry of complexes containing Pt--H, Pt--SH, or Pt--S fragments: from their apparent simplicity to the maze of reactions underlying their interconversion.

The relevance of platinum in the reaction of thiophene and derivatives with homogeneous transition-metal complexes as models for hydrodesulfurization has led us to the study of the reaction chemistry of complexes containing Pt--H, Pt--SH, and Pt--S fragments. Exploration of the reactions triggered by addition of controlled amounts of Na2S or NaSH to [Pt2(H)2(mu-H)(dppp)2]ClO4 (1) has provided evidence of the formation of complexes [Pt2(mu-H)(mu-S)(dppp)2]ClO4 (2), [Pt(H)(SH)(dppp)] (3), [Pt2(mu-S)2(dppp)2] (4), [Pt2(mu-S)(dppp)2] (5) and [Pt(SH)2(dppp)], in which dppp denotes 1,3-bis(diphenylphosphanyl)propane. Consequently, complexes 1, 2, and 5 as well as the already reported 3, 4, and [Pt(SH)2(dppp)] have been obtained and fully characterized spectroscopically. Also the crystal structures of 1 and 2 have been solved. Complexes 1-5 constitute the main framework of the network of reactions that account for the evolution of 1 under various experimental conditions as shown in Scheme 1. Apparently, this network has complexes 2 and 4 as dead-ends. However, their reciprocal interconversion by means of the replacement of one bridging hydride or sulfide ligand in the respective {Pt(mu-H)(mu-S)Pt} and {Pt(mu-S)2Pt} cores enables the closure of the reaction cycle involving complexes 1-5. Theoretical calculations support the existence of the undetected intermediates proposed for conversion from 1 to 2 and from 3 to 2 and also account for the fluxional behavior of 1 in solution. The intermediates proposed are consistent with the experimental results obtained in comparable reactions carried out with labeled reagents, which have provided evidence that complex 1 is the source of the hydride ligands in complexes 2 and 3. Overall, our results show the strong dependence on the experimental conditions for the formation of complexes 1-5 as well as for their further conversion in solution.

Journal Article↗

PubMed2006

Hydrogen electrocatalysis.

A selection of recent theoretical and experimental studies on electrolytic hydrogen evolution is presented. It is demonstrated with well-defined model surfaces that this reaction is a very structure-sensitive process. Crystallographic orientation, defect density and surface composition are parameters that determine the local geometric and electronic surface structure, and are thus crucial for the electrocatalytic activity as characterised by the exchange current density. The observed trends can be understood within a recent theory by J. K. Nørskov et al., which is based on density functional calculations and which emphasises the impact of hydrogen chemisorption energies on the reaction rate, that is, on the exchange current density. The particular electrocatalytic activities of ultrathin metal films and of nanostructures are addressed.

Journal Article↗

PubMed2002

Theoretical prediction and experimental determination of the effect of mold characteristics on temperature and monomer conversion fraction profiles during polymerization of a PMMA-based bone cement.

The present work is concerned with applications of a kinetic model for free-radical polymerization of a polymethylmethacrylate-based bone cement. Autocatalytic behavior at the first part of the reaction as well as a diffusion control phenomenon near vitrification are described by the model. Comparison of theoretical computations with experimental measurements for the temperature evolution during batch casting demonstrated the capacity of the proposed model to represent the kinetic behavior of the polymerization reaction. Temperature evolution and monomer conversion were simulated for the cure of the cement in molds made of different materials. The maximum monomer conversion fraction was markedly influenced by the physical properties of the mold material. The unreacted monomer acts as a plasticizer that influences the mechanical behavior of the cement. Hence, the same cement formulation cured in molds of different materials may result in different mechanical response because of the differences in the amounts of residual monomer. Standardization of the mold type to prepare specimens for the mechanical characterization of bone cements is recommended. Theoretical prediction of temperature evolution during hip replacement indicated that for cement thickness lower than 6 mm the peak temperature at the bone-cement interface was below the limit stated for thermal injury (50 degrees C for more than 1 min). The use of thin cement layers is recommended to diminish the risk of thermal injury; however, it is accompanied by an increase in the amount of unreacted monomer present in the cured material.

Arthroplasty, Replacement, Hip↗