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Results for “regulatory evolution”

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PubMed1985

Stimulation of beta(1----3)glucan synthetase of various fungi by nucleoside triphosphates: generalized regulatory mechanism for cell wall biosynthesis.

Particulate fractions from the taxonomically diverse fungi Achlya ambisexualis, Hansenula anomala, Neurospora crassa, Cryptococcus laurentii, Schizophyllum commune, and Wangiella dermatitidis were found to catalyze the time-dependent incorporation of glucose from UDP-[14C]glucose into a water-insoluble material. The reaction was stimulated by bovine serum albumin. The product was characterized as beta(1----3)glucan on the basis of its resistance to alpha- and beta-amylase and susceptibility to beta(1----3)glucanase. With the exception of the preparation from A. ambisexualis, all others were stimulated by nucleoside triphosphates and their analogs. The best activators were GTP and guanosine 5'-(gamma-thio)triphosphate. It is concluded that the stimulation by nucleotides, previously found with the glucan synthetase of Saccharomyces cerevisiae, is a regulatory mechanism that was well conserved during fungal evolution, presumably because of its importance in controlling cell wall biosynthesis and cell growth.

Cell Wall↗

PubMed2003

Multi-species sequence comparison: the next frontier in genome annotation.

Multi-species comparisons of DNA sequences are more powerful for discovering functional sequences than pairwise DNA sequence comparisons. Most current computational tools have been designed for pairwise comparisons, and efficient extension of these tools to multiple species will require knowledge of the ideal evolutionary distance to choose and the development of new algorithms for alignment, analysis of conservation, and visualization of results.

Animals↗

PubMed2003

Shielding the double-edged sword: negative regulation of the innate immune system.

The innate immune system is evolutionarily conserved among all multicellular organisms and is the first line of defense against microorganisms. It enables the host not only to combat pathogenic organisms but also to cohabit with nonpathogenic microorganisms by balancing the host-microorganism interaction. The innate immune response is activated rapidly (within hours) compared with adaptive immunity. Activation of the innate immune system allows the activation of the adaptive immune response by production of proinflammatory cytokines and by providing stimulatory signals via major histocompatibility complex molecules and costimulatory molecules such as CD40, CD80, or CD86; together, these lead to the full activation of both immune systems to fight against pathogenic microorganisms. Activation of the innate immune system, however, can be a double-edged sword for the host. Proinflammatory cytokines mediate a positive feedback loop on the innate immune system, and overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes such as hyperthermia, organ failure, and even death in extreme cases. Moreover, if the overproduction of proinflammatory cytokines persists, it may cause chronic inflammatory diseases. During evolution, the innate immune system has acquired complicated regulatory systems to control itself so that this "sword" will not kill the host. Various mechanisms including inhibition of Toll-like receptor signaling by interleukin-1 receptor-associated kinase-M have evolved for this purpose and are important not only to fight against pathogenic microorganisms efficiently but also are critical for the peaceful coexistence with commensal bacterial flora.

Animals↗

PubMed2000

RNAi analysis of Deformed, proboscipedia and Sex combs reduced in the milkweed bug Oncopeltus fasciatus: novel roles for Hox genes in the hemipteran head.

Insects have evolved a large variety of specialized feeding strategies, with a corresponding variability in mouthpart morphology. We have, however, little understanding of the developmental mechanisms that underlie this diversity. Until recently it was difficult to perform any analysis of gene function outside of the genetic model insects Drosophila melanogaster and Tribolium castaneum. In this paper, we report the use of dsRNA-mediated interference (RNAi) to dissect gene function in the development of the milkweed bug Oncopeltus fasciatus, which has specialized suctorial mouthparts. The Hox genes Deformed (Dfd), proboscipedia (pb) and Sex combs reduced (Scr) have previously been shown to be expressed in the gnathal appendages of this species. Strikingly, the milkweed bug was found to have an unusual expression pattern of pb. Here, by analyzing single and combination RNAi depletions, we find that Dfd, pb and Scr are used in the milkweed bug to specify the identity of the mouthparts. The exact roles of the genes, however, are different from what is known in the two genetic model insects. The maxillary appendages in the bug are determined by the activities of the genes Dfd and Scr, rather than Dfd and pb as in the fly and beetle. The mandibular appendages are specified by Dfd, but their unique morphology in Oncopeltus suggests that Dfd's target genes are different. As in flies and beetles, the labium is specified by the combined activities of pb and Scr, but again, the function of pb appears to be different. Additionally, the regulatory control of pb by the other two genes seems to be different in the bug than in either of the other species. These novelties in Hox function, expression pattern and regulatory relationships may have been important for the evolution of the unique Hemipteran head.

Animals↗

PubMed2006

Evolutionary potential of a duplicated repressor-operator pair: simulating pathways using mutation data.

Ample evidence has accumulated for the evolutionary importance of duplication events. However, little is known about the ensuing step-by-step divergence process and the selective conditions that allow it to progress. Here we present a computational study on the divergence of two repressors after duplication. A central feature of our approach is that intermediate phenotypes can be quantified through the use of in vivo measured repression strengths of Escherichia coli lac mutants. Evolutionary pathways are constructed by multiple rounds of single base pair substitutions and selection for tight and independent binding. Our analysis indicates that when a duplicated repressor co-diverges together with its binding site, the fitness landscape allows funneling to a new regulatory interaction with early increases in fitness. We find that neutral mutations do not play an essential role, which is important for substantial divergence probabilities. By varying the selective pressure we can pinpoint the necessary ingredients for the observed divergence. Our findings underscore the importance of coevolutionary mechanisms in regulatory networks, and should be relevant for the evolution of protein-DNA as well as protein-protein interactions.

Computational Biology↗

PubMed2006

On the discovery and development of CFTR chloride channel activators.

Chloride channels play important roles in vital cellular signalling processes contributing to homeostasis in both excitable and non-excitable cells. Since 1987, more than ten ion channel genes have been identified as causing human hereditary diseases among them the genes for the voltage-dependent chloride channel ClC-1 (myotonia) and the cystic fibrosis transmembrane conductance regulator (CFTR) protein (cystic fibrosis). The CFTR gene was cloned in 1989 and its protein product identified as an ATP-gated and phosphorylation-regulated chloride channel during the following two years. Since then, searching for potent and specific small molecules able to modulate normal and mutated CFTR has become a crucial endpoint in the field for both our understanding of the physiological role that CFTR plays in epithelial cells and more importantly for the development of therapeutic agents to cure cystic fibrosis (CF). It is predicted that a pharmacological approach would help not only to restore the defective transport activity of mutant CFTR but also to correct the regulatory function of CFTR. This review describes the evolution of CFTR pharmacology and how during the last five years, high throughput screening assays have been developed to identify novel molecules, some of them probably constituting a reservoir of future therapeutic agents for CF.

Benzimidazoles↗

PubMed1978

Suppression of uterine motor activity by prostaglandin synthetase inhibitor Naproxen.

Rats were ovariectomized on day 16 of pregnancy and they were fitted with a pressure sensor uterine microballoon assembly and were given a daily dose of Naproxen-sodium. Daily uterine activity recordings were taken and subjected to statistical analysis and the rats were carefully checked for either aborting or delivering their fetuses. Our data showed that Naproxen treatment effectively and significantly prevented the autocatalytic evolution of the uterine motor activity and the regulatory "see-saw" of progesterone and prostaglandins was rebalanced at a lower level.

Animals↗

PubMed2001

Fibrin sealant: clinical use and the development of the University of Virginia Tissue Adhesive Center.

The utilization of fibrin sealants to augment hemostasis, seal tissues, and facilitate targeted delivery of drugs is increasing. In 1985, a hospital-based program was established to provide autologous and allogeneic cryoprecipitate that serves as a fibrin sealant when combined with bovine thrombin. To date, more than 4,000 patients have been treated with this product at our institution, with an efficacy rate greater than 90%. Collaboration among surgical services and the blood bank fostered multispecialty expertise with this product that led, in 1997, to the establishment of the University of Virginia Tissue Adhesive Center. The Tissue Adhesive Center is a multidisciplinary center whose physician director and nursing and administrative support staff facilitate basic research, laboratory investigation, and preclinical and clinical trials with collaborators throughout the university. The Tissue Adhesive Center also provides educational programs and clinical consultation, and tracks and participates in peer review of sealant use. The licensure of a commercially produced, virally inactivated, pooled-plasma fibrin sealant in May 1998 provided an alternative source of adhesive. Utilization of the commercial product surpassed use of the blood bank product in April 1999. At present, use of the commercial product is approximately 3 times that of the blood bank-produced sealant. This report reviews the clinical uses of fibrin sealant, its regulatory history, the production of fibrin sealants, the evolution of a blood bank fibrin sealant program, the development of the Tissue Adhesive Center, and the utilization of commercial and blood bank-produced sealant at our university hospital.

Education, Medical, Continuing↗

PubMed2006

Plasticity of physiology in Lobelia: testing for adaptation and constraint.

Phenotypic plasticity is thought to be a major mechanism allowing sessile organisms such as plants to adapt to environmental heterogeneity. However, the adaptive value of many common plastic responses has not been tested by linking these responses to fitness. Even when plasticity is adaptive, costs of plasticity, such as the energy necessary to maintain regulatory pathways for plastic responses, may constrain its evolution. We used a greenhouse experiment to test whether plastic physiological responses to soil water availability (wet vs. dry conditions) were adaptive and/or costly in the congeneric wildflowers Lobelia cardinalis and L. siphilitica. Eight physiological traits related to carbon and water uptake were measured. Specific leaf area (SLA), photosynthetic rate (A), stomatal conductance (gs), and photosynthetic capacity (Amax) responded plastically to soil water availability in L. cardinalis. Plasticity in Amax was maladaptive, plasticity in A and g(s) was adaptive, and plasticity in SLA was adaptively neutral. The nature of adaptive plasticity in L. cardinalis, however, differed from previous studies. Lobelia cardinalis plants with more conservative water use, characterized by lower g(s), did not have higher fitness under drought conditions. Instead, well-watered L. cardinalis that had higher g(s) had higher fitness. Only Amax responded plastically to drought in L. siphilitica, and this response was adaptively neutral. We detected no costs of plasticity for any physiological trait in either L. cardinalis or L. siphilitica, suggesting that the evolution of plasticity in these traits would not be constrained by costs. Physiological responses to drought in plants are presumed to be adaptive, but our data suggest that much of this plasticity can be adaptively neutral or maladaptive.

Acclimatization↗

PubMed1986

The role of DTNB light chain in the contractile properties of skeletal muscle.

The mechanical and molecular dynamical properties of the glycerinated muscle fibres from m. psoas of rabbit were investigated after treatment with 5,5'-dithiobis/2-nitrobenzoate (DTNB). After DTNB treatment the fibre bundles shortened and exerted force in ATP-relaxing solution. The rate of the ATP hydrolysis in relaxation-inducing medium increased significantly after DTNB treatment, and simultaneously the amount of the LC2(DTNB) light chain decreased to 40 per cent of the original value measured by gel electrophoresis. The electron paramagnetic resonance spectra of muscle fibres labelled with maleimide spin label after DTNB treatment exhibited high degree of order of label in rigor, but this order decreased after shortening. The experiments support the assumption that, in vertebrate skeletal muscles, besides the troponin-tropomyosin regulation system which developed later in evolution, the LC2 light chain should maintain some regulatory properties.

Adenosine Triphosphatases↗

PubMed1993

[The physician in the pharmaceutical industry].

The physician's role in the pharmaceutical industry has changed over the past years. This change is a consequence of several factors, namely the evolution of the industry itself, the legislative and regulatory changes in this particular area, the development of medicine, new techniques and research, and finally the physician's needs. The changes that this activity has undergone not only create new stimuli for the physicians in the industry, but also new challenges and needs for the complete achievement of their career. This is a review article of the main functions and responsibilities of the physician in the pharmaceutical industry as well as the new challenges that this group of physicians faces. Finally, special attention is given to post-graduate courses and their relation with the academic structure.

Drug Industry↗

PubMed1993

Multiple changes in chromatin structure precede the transcriptional activation of the human growth hormone locus in placental cells.

In addition to the growth hormone gene (hGH-N) itself, the human growth hormone (hGH) locus contains four related genes, namely hGH-V and hCS-L, -A and -B, which have appeared very recently in evolution and are specifically expressed in placenta. With the aim of identifying the regulatory elements responsible for this placental-specific expression, we have mapped the DNaseI hypersensitive sites present at the hGH gene cluster in a placental cell line (BeWo) that expresses the hGH-V and hCS genes. Our results reveal a complex pattern of hypersensitive sites distributed along the hGH locus, most of which appear to be cell type-specific. Thus, we have identified placental-specific hypersensitive sites within the first intron of the hGH-N and hGH-V genes, but not in the equivalent regions of the hCS genes. In addition, we have found several placental-specific hypersensitive sites downstream of the hCS-L and hCS-A genes, which might reflect the presence of enhancer elements similar to that located downstream of the hCS-B gene (Walker et al. (1990) J. Biol. Chem. 265, 12940). Comparison of BeWo cells with a placental cell line (JEG-3) which does not express the hGH-V and hCS genes revealed a very similar pattern of hypersensitive sites, suggesting that the sites detected are established before the onset of transcription. Our results indicate that the transition to an active hGH locus in placental cells requires multiple alterations in chromatin structure, and provide a framework for the molecular analysis of the regulatory elements and mechanisms mediating such processes.

Biological Evolution↗

PubMed2004

Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans.

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

Animals↗

PubMedDate not supplied

Developmental mechanisms of threshold evolution in a polyphenic beetle.

Polyphenic development is thought to play a pivotal role in the origin of morphological novelties. However, little is known about how polyphenisms evolve in natural populations, the developmental mechanisms that may mediate such evolution, and the consequences of such modification for patterns of morphological variation. Here we examine the developmental mechanisms of polyphenism evolution in highly divergent natural populations of the dung beetle, Onthophagus taurus. Males of this species express two alternative morphologies in response to larval feeding conditions. Favorable conditions cause males to grow larger than a threshold body size and to develop a pair of horns on their heads. Males that encounter relatively poor conditions during larval life do not reach this threshold size and remain hornless. Exotic populations of O. taurus have diverged dramatically in body size thresholds in less than 40 years since introduction to new habitats, resulting in the expression of highly divergent and novel horn length-body size scaling relationships in these populations. Here we show that larvae of populations that have evolved a larger threshold body size (1) have to accumulate greater mass to become competent to express the horned morph, (2) require more time to complete the final instar, (3) are less sensitive to the juvenile hormone (JH) analogue methoprene, and (4) exhibit a delay in the sensitive period for methoprene relative to other developmental events. JH has been shown previously to control horn expression in this species. Our results show that threshold evolution may be mediated via changes in the degree and timing of sensitivity to JH and may result in correlated changes in the dynamics and duration of larval development. Strain-specific differences in JH sensitivity have previously been demonstrated in other insects. However, to the best of our knowledge this is the first demonstration that changes in the timing of the sensitive period for JH may play an equally important role in the evolution of novel thresholds. We discuss our findings in the context of the developmental regulatory mechanisms that underlie polyphenic development and use our results to explore the consequences of, and constraints on, polyphenism evolution in nature.

Animals↗

PubMed2004

Gene regulatory network analysis in sea urchin embryos.

It may safely be predicted that GRN analysis will become increasingly important. It will come to underlie the causal study of development, the major effort underway to understand the regulatory code built into animal genomes and also the evolution of these genomes. Partly by serendipity, sea urchin embryos turn out to be a superb experimental material for GRN analysis. Their natural properties have, in turn, influenced the predilections of those who work on them, and between them and us, so to speak, this is now a developmental system of which we are rapidly gaining an unusually complete understanding. The causal linkages that control development of the whole embryo will be revealed, leading all the way from the heritable genomic regulatory code to the events of embryology. The fundamental experimental operation is the perturbation analysis: Here is where causality permeates the exploration. We have in this chapter summarized in some detail the requirements for perturbation GRN analysis in sea urchin embryos. But that is not all, nor is it enough to enable the assembly of a GRN: What is required is the combined application of elegant computational methods, of gene regulation molecular biology, of genomic sequence data, and of experimental embryology. As the results crystallize together, we can begin to see how far this powerful combination of methods and ideas is going to carry us.

Animals↗

PubMed2000

New regulatory framework for wastewater quality control in Mexico.

This paper analyses the new regulatory framework for wastewater quality control developed in Mexico. It provides a description of the Mexican government strategies for water pollution control. The discussion focuses on the policy instruments used, their evolution and the main difficulties encountered in their implementation. The new regulatory framework is discussed highlighting some of the economic implications of the reforms. The paper concludes that proper institutional development and monitoring are essential factors for the success of any policy instrument for wastewater quality control.

Developing Countries↗

PubMed2002

Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci.

Fierce (frc) mice are deleted for nuclear receptor 2e1 (Nr2e1), and exhibit cerebral hypoplasia, blindness, and extreme aggression. To characterize the Nr2e1 locus, which may also contain the mouse kidney disease (kd) allele, we compared sequence from human, mouse, and the puffer fish Fugu rubripes. We identified a novel gene, c222389, containing conserved elements in noncoding regions. We also discovered a novel vertebrate gene conserved across its length in prokaryotes and invertebrates. Based on a dramatic upregulation in lactating breast, we named this gene lactation elevated-1 (LACE1). Two separate 100-bp elements within the first NR2E1 intron were virtually identical between the three species, despite an estimated 450 million years of divergent evolution. These elements represent strong candidates for functional NR2E1 regulatory elements in vertebrates. A high degree of conservation across NR2E1 combined with a lack of interspersed repeats suggests that an array of regulatory elements embedded within the gene is required for proper gene expression.

Alternative Splicing↗

PubMed1989

The domain model for eukaryotic DNA organization. 2: A molecular basis for constraints on development and evolution.

A model for eukaryotic DNA organization has been proposed in which DNA regulatory processes depend on multiple site-specific DNA-nuclear matrix interactions throughout a DNA domain. In this model gene regulation depends on combinations of a few control factors in a cell to activate cell type-specific genes. This model suggests simple molecular mechanisms for organismal development which can account for sequential activation of appropriate groups of genes throughout development and for specific constraints on developmental pathways. Additionally, these suggested developmental pathways are consistent with mechanisms of evolution in which gradualism and punctuated equilibrium are not exclusive of one another and are interrelated mechanisms of evolution that are both induced by specific chromosomal mutations.

Animals↗