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Results for “regulatory evolution”

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PubMed1998

Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells.

Autoimmune diseases can result from the breakdown of regulation and subsequent activation of self-antigenic determinant-reactive T cells. During the evolution of the autoimmune response to myelin basic protein (MBP) in B10.PL mice, several distinct T cell populations expand: the effectors mediating experimental autoimmune encephalomyelitis (EAE) are MBP-reactive, CD4+, and predominantly TCR Vbeta8.2+; in addition, at least two regulatory populations can be detected--one comprised of Vbeta14+ CD4 T cells, reactive to a framework region 3 determinant on the Vbeta8.2 chain, and a second that is CD8+ and reactive to another Vbeta8.2 determinant. The combined action of these two regulatory cell types controls disease-causing effectors, resulting in spontaneous recovery from disease. In this report, we reveal that the cytokine secretion pattern of TCR peptide-specific regulatory CD4 T cells can profoundly influence whether a type 1 or type 2 population predominates among MBP-specific CD4 effectors. The priming of type 1 regulatory T cells results in deviation of the Ag-specific effector T cell population in a type 2 direction and protection from disease. In contrast, induction of type 2 regulatory T cells results in exacerbation of EAE, poor recovery, and an increased frequency of type 1 effectors. Thus, the encephalitogenic potential of the MBP-reactive effector population is crucially and dominantly influenced by the cytokine secretion phenotype of regulatory CD4 T cells. These findings have important implications in understanding peripheral tolerance to self-Ags as well as in the design of TCR-based therapeutic approaches.

Administration, Intranasal↗

PubMed2006

One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity.

The genomic era has revealed that the large repertoire of observed animal phenotypes is dependent on changes in the expression patterns of a finite number of genes, which are mediated by a plethora of transcription factors (TFs) with distinct specificities. The dimerization of TFs can also increase the complexity of a genetic regulatory network manifold, by combining a small number of monomers into dimers with distinct functions. Therefore, studying the evolution of these dimerizing TFs is vital for understanding how complexity increased during animal evolution. We focus on the second largest family of dimerizing TFs, the basic-region leucine zipper (bZIP), and infer when it expanded and how bZIP DNA-binding and dimerization functions evolved during the major phases of animal evolution. Specifically, we classify the metazoan bZIPs into 19 families and confirm the ancient nature of at least 13 of these families, predating the split of the cnidaria. We observe fixation of a core dimerization network in the last common ancestor of protostomes-deuterostomes. This was followed by an expansion of the number of proteins in the network, but no major dimerization changes in interaction partners, during the emergence of vertebrates. In conclusion, the bZIPs are an excellent model with which to understand how DNA binding and protein interactions of TFs evolved during animal evolution.

Animals↗

PubMed2025

Comparative Genomic Screening Identifies Developmental Constraint Loci Underscoring the Phenotypic Evolution of Syngnathids.

Seahorses and their relatives (syngnathids) exhibit remarkable diversity in morphology and function, characterized by their distinctive body shapes and specialized feeding mechanisms. Despite recent advances in uncovering the genetic basis of some traits, the genotype-phenotype map in syngnathids remains incomplete. In this study, we employed forward-genomic approaches and developed a method to enrich for human disease amino acid loci at a genomic scale. Our aim was to identify genetic loci associated with fin size reduction, tooth loss, and spinal curvature in syngnathids. Intriguingly, we identified a convergent amino acid change in the lat4a gene shared by syngnathids and some flying fishes, with in vitro analysis confirming its role in fin size evolution in both lineages. While genes critical for tooth development are conserved in syngnathids, the absence of key regulatory elements, such as pitx2, likely contributes to tooth loss. Additionally, we implicated col6a3 in spinal curvature development in seadragons. These findings reveal novel genetic signatures and developmental constraints underlying syngnathid diversity, demonstrating the utility of comparative genomics and targeted gene enrichment in exploring vertebrate evolution.

Animals↗

PubMed1990

Functional elements and domains inferred from sequence comparisons of a heat shock gene in two nematodes.

Caenorhabditis elegans and Caenorhabditis briggsae are two closely related nematode species that are nearly identical morphologically. Interspecific cross-hybridizing DNA appears to be restricted primarily to coding regions. We compared portions of the hsp-3 homologs, two grp 78-like genes, from C. elegans and C. briggsae and detected regions of DNA identity in the coding region, the 5' flanking DNAs, and the introns. The hsp-3 homologs share approximately 98% and 93% identity at the amino acid and nucleotide levels, respectively. Using the nucleotide substitution rate at the silent third position of the codons, we have estimated a lower limit for the date of divergence between C. elegans and C. briggsae to be approximately 23-32 million years ago. The 5' flanking DNAs and one of the introns contain elements that are highly conserved between C. elegans and C. briggsae. Some of the regions of nucleotide identity in the 5' flanking DNAs correspond to previously detected identities including viral enhancer sequences, a heat shock element, and an element present in the regulatory regions of mammalian grp78 and grp94 genes. We propose that a comparison of C. elegans and C. briggsae sequences will be useful in the detection of potential regulatory and structural elements.

Amino Acid Sequence↗

PubMed1989

Dynamics of the marketplace: key issues, new linkages, and successful organizational models in academic CME.

Following an initial description of the marketplace for CME, the article identifies and explores six key issues for the future of academic CME: evolution of the academic health center; practice changes and reimbursement; impact of technology; regulatory influences; proliferation of CME providers; and medical school leadership. The author then turns to a discussion of new ways to link CME with practitioners--through academic health centers, within various practice environments, through technology, in the regulatory arena, and by developing relationships with competing groups and organizations. Finally, the article suggests several organizational models with potential for expanding these linkages.

Academic Medical Centers↗

PubMed2002

Inhibition of skeletal muscle development: less differentiation gives more muscle.

The fact that stem cells have to be protected from premature differentiation is true for many organs in the developing embryo and the adult organism. However, there are several arguments that this is particularly important for (skeletal) muscle. There are some evolutionary arguments that muscle is a "default" pathway for mesodermal cells, which has to be actively prevented in order to allow cells to differentiate into other tissues. Myogenic cells originate from very small areas of the embryo where only a minor portion of these cells is supposed to differentiate. Differentiated muscle fibres are unconditionally post-mitotic, leaving undifferentiated stem cells as the only source of regeneration. The mechanical usage of muscle and its superficial location in the vertebrate body makes regeneration a frequently used mechanism. Looking at the different inhibitory mechanisms that have been found within the past 10 or so years, it appears as if evolution has taken this issue very serious. At all possible levels we find regulatory mechanisms that help to fine tune the differentiation of myogenic cells. Secreted molecules specifying different populations of somitic cells, diffusing or membrane-bound signals among fellow myoblasts, modulating molecules within the extracellular matrix and last, but not least, a changing set of activating and repressing cofactors. We have come a long way from the simple model of MyoD just to be turned on at the right time in the right cell.

Animals↗

PubMed1996

Genomes with distinct function composition.

The functional composition of organisms can be analysed for the first time with the appearance of complete or sizeable parts of various genomes. We have reduced the problem of protein function classification to a simple scheme with three classes of protein function: energy-, information- and communication-associated proteins. Finer classification schemes can be easily mapped to the above three classes. To deal with the vast amount of information, a system for automatic function classification using database annotations has been developed. The system is able to classify correctly about 80% of the query sequences with annotations. Using this system, we can analyse samples from the genomes of the most represented species in sequence databases and compare their genomic composition. The similarities and differences for different taxonomic groups are strikingly intuitive. Viruses have the highest proportion of proteins involved in the control and expression of genetic information. Bacteria have the highest proportion of their genes dedicated to the production of proteins associated with small molecule transformations and transport. Animals have a very large proportion of proteins associated with intra- and intercellular communication and other regulatory processes. In general, the proportion of communication-related proteins increases during evolution, indicating trends that led to the emergence of the eukaryotic cell and later the transition from unicellular to multicellular organisms.

Animals↗

PubMed1988

Hepatocyte-specific promoter element HP1 of the Xenopus albumin gene interacts with transcriptional factors of mammalian hepatocytes.

By transfecting various Xenopus albumin-CAT fusion genes into the mouse hepatoma cell line BW1J a 13 base-pair hepatocyte-specific promoter element (HP1) could be identified. A similar sequence element is also present in the promoter of the albumin and alpha-fetoprotein genes of other vertebrates. Introduction of single point mutations into HP1 destroys its function. Binding studies with nuclear proteins identify a factor interacting with HP1 which is specific for hepatic cells. In-vitro transcription in a rat liver nuclear extract demonstrates that HP1 leads to an increased transcriptional activity. This increased transcription is specifically inhibited by the addition of an HP1-containing oligonucleotide, establishing that the interaction of factors with HP1 is essential for increased transcription. Since HP1 derived from a Xenopus gene functions in mammalian hepatocytes, we conclude that a regulatory system involved in liver-specific gene expression has been conserved during evolution.

Albumins↗

PubMed1983

Thyroid hormones in cyclostomes and fish and their role in regulation of intermediary metabolism.

1. Experimental data obtained in cyclostomes and fish concerning the plasma levels of thyroxine and tri-iodothyronine as well as their influence on intermediary metabolism of lipids, carbohydrates, and proteins are reviewed. 2. The information dealing with the physiological role of thyroid hormones in regulation of metabolic processes seems to be scarce in cyclostomes and controversial in fishes. 3. Nevertheless, the data covered in the review support the generalization that thyroid hormones, probably along with some other hormones, exert a regulatory action on the metabolic processes already on the lower stage of the evolution of poikilothermic vertebrates.

Animals↗

PubMed1982

The comparative isozymology of vertebrate hexokinases.

1. Multiple hexokinase isozymes have been found in most vertebrates. Since each isozyme displays distinctive structural, kinetic and regulatory characteristics, the system qualifies as a useful probe for studies on molecular evolution. 2. At least seven types of chromatographic patterns of liver hexokinases have been observed in mammals. In contrast, each Class of lower vertebrates present only two or three distinct profiles. 3. Aves and higher Reptiles do not have the same hexokinase isozymes as other vertebrates. The nature of the differences is poorly understood. 4. Ontogenetic changes of liver hexokinase profiles are quite different in rat, chick and frog. 5. Structural comparisons of three vertebrate hexokinases having a molecular weight of approximately 100,000 suggest that those isozymes originated from a pre-vertebrate ancestor through gene duplication followed by fusion and further duplication events. Another hexokinase (the so-called glucokinase), with half the molecular weight, may have arisen either as the result of subsequent even splitting of the fused gene or, less probably, by divergence from a duplicated gene before the fusion event.

Amphibians↗

PubMed2006

The tumor microenvironment in the post-PAGET era.

The research area of tumor microenvironment is considered, at present, to be an important factor in tumorigenesis and especially in tumor progression. The present mini review is focused on three principles characterizing the nature of the tumor microenvironment. We first discuss the regulatory functions of the tumor microenvironment and the complexity of the combinatorial signaling pathways operating in it. We then address the aspect that the tumor microenvironment incorporates both pro and anti malignancy factors and that a balance between these factors regulates tumor progression. Thirdly we provide evidence that the non-tumor cells in the tumor microenvironment and their products may be different from those of their counterparts residing in non-tumor microenvironments. The conclusion of this mini review is that the tumor microenvironment, by exerting regulatory functions and selective pressures drives cancer cells into one of several molecular evolution pathways thereby determining and shaping their malignancy phenotype.

Cell Transformation, Neoplastic↗

PubMed2005

Homeland security challenges in nursing practice.

Nurses need a comprehensive knowledge of doctrine, laws, regulations,programs, and processes that build the operational framework for health care preparedness. Key components of this knowledge base reside in the areas of: evolution of homeland security: laws and mandates affecting health care and compliance and regulatory issues for health care organizations. This article addresses primary components in both of these areas, after first assessing the status of nursing's involvement (in homeland security), as portrayed in the professional literature.

Civil Defense↗

PubMed1992

The 1-aminocyclopropane-1-carboxylate synthase gene family of Arabidopsis thaliana.

Genomic sequences encoding five divergent 1-aminocyclopropane-1-carboxylic acid (ACC) synthase polypeptides (ACC1, ACC2, ACC3, ACC4, and ACC5) have been isolated from Arabidopsis thaliana by using heterologous cDNAs and PCR fragments amplified from genomic DNA with degenerate oligonucleotide primers. Each gene is located on a different chromosome in the Arabidopsis genome. The genes are differentially expressed during development and in response to environmental stimuli. Protein-synthesis inhibition derepresses the expression of all genes but most dramatically derepresses that of ACC2, suggesting that their expression may be under negative control. The sequence of ACC2 was determined, and its transcription initiation site was defined. Authenticity of the polypeptide encoded by the gene was confirmed by expression experiments in Escherichia coli. The predicted size of the protein is 55,623 Da, and it contains the 11 invariant amino acid residues conserved between aminotransferases and ACC synthases from various plant species. Comparative analysis of structural and expression characteristics of ACC synthase genes from Arabidopsis and other plant species suggests that the sequence divergence of the ACC synthase genes and possibly the distinct regulatory networks governing the expression of ACC synthase subfamilies arose early in plant evolution and before the divergence of monocots and dicots.

Amino Acid Sequence↗

PubMed2006

Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.

Eye development initiates as an evagination of the early neural plate, before the closure of the neural tube. Structural malformations of the eye such as anophthalmia and microphthalmia arise very early in development. It is not surprising therefore that three of the genes currently identified to play a significant role in these developmental eye anomalies are also major players in brain development and regionalization. However, as has been emerging for a high proportion of transcriptional regulators studied, these genes have evolved to play multiple roles throughout development, and perhaps even in adult tissue maintenance. This complex spatiotemporal expression pattern requires elaborate regulatory systems which we are beginning to unravel. A major component of these complex regulatory networks is a series of cis-acting elements, highly conserved through evolution, which spread large distances from the coding region of each gene. We describe how cross regulation for PAX6, SOX2 and perhaps OTX2 has now been uncovered, pointing to the mechanisms that can fine-tune the expression of such essential developmental components. These interactions also help us understand why there is significant phenotypic overlap between mutations at these three loci.

Animals↗

PubMed2002

The principles of validation and the ECVAM validation process.

The validation of a test method is the process by which the relevance and reliability of the method are assessed for a particular purpose. It is an essential stage in the evolution of the method from its development to its acceptance and application for regulatory purposes. The principles according to which alternative tests should be validated have been agreed at an international level, although the actual process by which the validation process is conducted varies between different validation authorities. This paper summarises the principles of alternative test development and validation, and describes how the principles have been applied to the validation of in vitro tests by ECVAM.

Animal Testing Alternatives↗

PubMed2005

A Plasmodium whole-genome synteny map: indels and synteny breakpoints as foci for species-specific genes.

Whole-genome comparisons are highly informative regarding genome evolution and can reveal the conservation of genome organization and gene content, gene regulatory elements, and presence of species-specific genes. Initial comparative genome analyses of the human malaria parasite Plasmodium falciparum and rodent malaria parasites (RMPs) revealed a core set of 4,500 Plasmodium orthologs located in the highly syntenic central regions of the chromosomes that sharply defined the boundaries of the variable subtelomeric regions. We used composite RMP contigs, based on partial DNA sequences of three RMPs, to generate a whole-genome synteny map of P. falciparum and the RMPs. The core regions of the 14 chromosomes of P. falciparum and the RMPs are organized in 36 synteny blocks, representing groups of genes that have been stably inherited since these malaria species diverged, but whose relative organization has altered as a result of a predicted minimum of 15 recombination events. P. falciparum-specific genes and gene families are found in the variable subtelomeric regions (575 genes), at synteny breakpoints (42 genes), and as intrasyntenic indels (126 genes). Of the 168 non-subtelomeric P. falciparum genes, including two newly discovered gene families, 68% are predicted to be exported to the surface of the blood stage parasite or infected erythrocyte. Chromosomal rearrangements are implicated in the generation and dispersal of P. falciparum-specific gene families, including one encoding receptor-associated protein kinases. The data show that both synteny breakpoints and intrasyntenic indels can be foci for species-specific genes with a predicted role in host-parasite interactions and suggest that, besides rearrangements in the subtelomeric regions, chromosomal rearrangements may also be involved in the generation of species-specific gene families. A majority of these genes are expressed in blood stages, suggesting that the vertebrate host exerts a greater selective pressure than the mosquito vector, resulting in the acquisition of diversity.

Animals↗

PubMed2000

[Better understanding of the biology of cancer cells].

Most forms of cancer arise through a Darwinian evolutionary process. The natural selection that ultimately leads to cancer takes place in somatic tissues although it may be triggered by inherited mutations in a small but significant minority. It favors the growth of clones and subclones that are less and less responsive to normal intra- and extracellular growth control mechanisms. The development of molecular biology has led to the identification of many genes that participate in this somatic evolution. They belong to the following groups: Oncogenes, constitutively activated by structural and/or regulatory changes that drive the cell to continuous proliferation; Tumor suppressor genes, that can inhibit the illegitimately activated cell cycle. They contribute to tumor development by loss mutations or permanent down-regulation, e.g. by methylation; Apoptosis inhibitory genes that can contribute to tumor development by raising the apoptotic threshold, and apoptosis promoting genes that can favor the growth of apoptosis prone tumor cells by their loss or inactivation; DNA repair genes whose inactivation can counteract the normal elimination of cells that carry potentially cancer promoting mutations. Inherited mutations in DNA repair genes can lead to familial cancer syndromes. Immortalizing genes that counteract cellular senescence; Angiogenesis promoting genes whose products may stimulate the vascular supply of tumors; Genes whose structural or functional changes may facilitate the escape of tumor cells from immune rejection; The multi-step development of individual tumors can encompass changes in most or all of these genes. They occur independently of each other and without any fixed order or timing. Tumor emancipation from growth control can therefore proceed along various pathways. It follows that each tumor must be regarded as a biologically unique individual.

Apoptosis↗

PubMed2000

[Better understanding of the biology of cancer cells].

Apoptosis↗