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PubMed2001

Design principles for elementary gene circuits: Elements, methods, and examples.

The control of gene expression involves complex circuits that exhibit enormous variation in design. For years the most convenient explanation for these variations was historical accident. According to this view, evolution is a haphazard process in which many different designs are generated by chance; there are many ways to accomplish the same thing, and so no further meaning can be attached to such different but equivalent designs. In recent years a more satisfying explanation based on design principles has been found for at least certain aspects of gene circuitry. By design principle we mean a rule that characterizes some biological feature exhibited by a class of systems such that discovery of the rule allows one not only to understand known instances but also to predict new instances within the class. The central importance of gene regulation in modern molecular biology provides strong motivation to search for more of these underlying design principles. The search is in its infancy and there are undoubtedly many design principles that remain to be discovered. The focus of this three-part review will be the class of elementary gene circuits in bacteria. The first part reviews several elements of design that enter into the characterization of elementary gene circuits in prokaryotic organisms. Each of these elements exhibits a variety of realizations whose meaning is generally unclear. The second part reviews mathematical methods used to represent, analyze, and compare alternative designs. Emphasis is placed on particular methods that have been used successfully to identify design principles for elementary gene circuits. The third part reviews four design principles that make specific predictions regarding (1) two alternative modes of gene control, (2) three patterns of coupling gene expression in elementary circuits, (3) two types of switches in inducible gene circuits, and (4) the realizability of alternative gene circuits and their response to phased environmental cues. In each case, the predictions are supported by experimental evidence. These results are important for understanding the function, design, and evolution of elementary gene circuits. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed1997

A study of oligonucleotide occurrence distributions in DNA coding segments.

In this paper we present a general strategy designed to study the occurrence frequency distributions of oligonucleotides in DNA coding segments and to deal with the problem of detecting possible patterns of genomic compositional inhomogeneities and disuniformities. Identifying specific tendencies or peculiar deviations in the distributions of the effective occurrence frequencies of oligonucleotides, with respect to what can be a priori expected, is of the greatest importance in biology. Differences between expected and actual distributions may in fact suggest or confirm the existence of specific biological mechanisms related to them. Similarly, a marked deviation in the occurrence frequency of an oligonucleotide may suggest that it belongs to the class of so-called "DNA signal (target) sequences". The approach we have elaborated is innovative in various aspects. Firstly, the analysis of the genomic data is carried out in the light of the observation that the distribution of the four nucleotides along the coding regions of the genoma is biased by the existence of a well-defined "reading frame". Secondly, the "experimental" numbers found by counting the occurrences of the various oligonucleotide sequences are appropriately corrected for the many kinds of mistakes and redundancies present in the available genetic Data Bases. A methodologically significant further improvement of our approach over the existing searching strategies is represented by the fact that, in order to decide whether or not the (corrected) "experimental" value of the occurrence frequency of a given oligonucleotide is within statistical expectations, a measure of the strength of the selective pressure, having acted on it in the course of the evolution, is assigned to the sequence, in a way that takes into account both the value of the "experimental" occurrence frequency of the sequence and the magnitude of the probability that this number might be the result of statistical fluctuations. If the strength of the selective pressure evaluated in this fashion turns out to be sufficiently large, the corresponding sequence will be considered to have an occurrence frequency beyond expectations and, hence, to be statistically and biologically interesting.

Algorithms↗
PubMed2003

Modeling of host genetics and resistance to infectious diseases: understanding and controlling nematode infections.

This paper considers approaches to modeling the dynamics of infectious disease and the application of such models to nematode parasite infections in ruminants. Particularly, these models are developed to account for host genetics and may be used to assess the effects of using genetics to control nematode infections. Three main issues are critically examined: the infection transmission cycle from pasture to host to pasture, the expected genetic relationships between resistance and performance, and the risks of parasite evolution in response to genetic changes in the host. To obtain answers that are realistic and of practical use, the modeling approaches require a solid grounding in biology. This biology is formalized and described using mathematical techniques, with the models parameterized using experimental or field data. Transmission dynamics have been quantified by modeling and are backed by strong experimental data. Selection for resistance will be successful in reducing egg output, pasture larval contamination and hence subsequent larval challenge. Modeling frameworks have been developed to predict genetic relationships between resistance to infectious disease and performance in general, and genetic correlations predicted for nematode resistance are close to mean published values. These predicted correlations strengthen as the larval challenge increases and the dietary (protein) adequacy decreases, however modeling challenges remain. Lastly, although convincing experimental data is not yet available, arguments based on modeling suggest that the risks of parasite evolution in response to genetic changes in the host should be less than the risks arising from other control strategies, such as anthelmintics. Thus, modeling techniques predict that selective breeding for resistance should be an effective and sustainable complementary control measure.

Animals↗
PubMed2006

Luminescence dynamics of terbium monodipicolinate in ethyl ammonium nitrate.

Energy level dynamics are experimentally examined for terbium monodipicolinate dissolved in ethyl ammonium nitrate (EAN). The luminescence lifetime, the luminescence risetime, and the absorption spectrum of terbium monodipicolinate in EAN are measured. The risetime of luminescence in terbium dipicolinate is experimentally shown to be nonzero and measurable. A dynamic model is presented that describes the evolution of terbium dipicolinate luminescence in EAN. The long risetime in the model is caused by a resonance between the 5E6 state in the terbium cation and the lowest triplet state (T1) in the dipicolinate anion. Bacterial endospore components dissolved in EAN are used to check the time resolution of the experimental apparatus. EAN is discussed partly because it is a room-temperature ionic liquid (RTIL), which is a class of solvents that may be useful for detecting bacterial endospores in the atmosphere.

Computer Simulation↗
PubMed1994

Heavy-ion induced genetic changes and evolution processes.

On Moon and Mars, there will be more galactic cosmic rays and higher radiation doses than on earth. Our experimental studies showed that heavy ion radiation can effectively cause mutation and chromosome aberrations and that high-LET heavy-ion induced mutants can be irreversible. Chromosome translocations and deletions are common in cells irradiated by heavy particles, and ionizing radiations are effective in causing hyperploidy. The importance of the genetic changes in the evolution of life is an interesting question. Through evolution, there is an increase of DNA content in cells from lower forms of life to higher organisms. The DNA content, however, reached a plateau in vertebrates. By increasing DNA content, there can be an increase of information in the cell. For a given DNA content, the quality of information can be changed by rearranging the DNA. Because radiation can cause hyperploidy, an increase of DNA content in cells, and can induce DNA rearrangement, it is likely that the evolution of life on Mars will be effected by its radiation environment. A simple analysis shows that the radiation level on Mars may cause a mutation frequency comparable to that of the spontaneous mutation rate on Earth. To the extent that mutation plays a role in adaptation, radiation alone on Mars may thus provide sufficient mutation for the evolution of life.

Animals↗
PubMed1989

Acute pancreatitis after experimental pancreatic transplantation.

We describe our serendipitous finding of a transplantation model of hemorrhagic pancreatic necrosis. The slow evolution, from edematous interstitial pancreatitis to hemorrhagic necrosis over the course of 8 days made the model amenable to therapeutic manipulation. The possible pathogenesis is discussed with reference to the published literature. From comparisons between the histologic and biochemical features of isografts and allografts, we suggest that ischemia-reperfusion injury initiates pancreatitis through oxygen-free radicals, and that the transformation to hemorrhagic pancreatic necrosis in allografts reflects the involvement of chemotactic immune factors and extracellular secretions from activated proteases.

Acute Disease↗
PubMed1990

An improved distribution of codon frequencies allowing for inhomogeneity of DNA's primary-structure evolution.

This is a sequel to the paper, where a model which describes ranged series of codon frequencies was proposed. The model was tested against the empirical distributions obtained for the best studied species and was on the whole found to be in fairly good agreement with the available data. The few deviations from the model's predictions were found to have a monotypic regularity. In the present paper we proceed on the assumption that the deviations are due to inhomogeneous conditions of molecular evolution within a genome. This approach makes it possible to elaborate the theory presented earlier. An improved model is derived for the ranged distribution of codon frequencies, which is then tested against the experimental data.

Base Sequence↗
PubMed2006

Pollinator response to female and male floral display in a monoecious species and its implications for the evolution of floral dimorphism.

Pollinator-mediated selection has been hypothesized as one cause of size dimorphism between female and male flowers. Flower number, ignored in studies of floral dimorphism, may interact with flower size to affect pollinator selectivity. In the present study, we explored pollinator response, and estimated pollen receipt and removal, in experimental populations of monoecious Sagittaria trifolia, in which plants were manipulated to display three, six, nine or 12 female or male flowers per plant. In this species, female flowers are smaller but have a more compressed flowering period than males, creating larger female floral displays. Overall, pollinators preferred to visit male rather than female displays of the same size. Both first visit per foraging bout and visitation rates to female displays increased with display size. However, large male displays did not show increased attractiveness to pollinators. A predicted relationship that pollen removal, rather than pollen receipt, is limited by pollinator visitation was confirmed in the experimental populations. The results suggest that the lack of selection on large male displays may affect the evolution of floral dimorphism in this species.

Animals↗
PubMed2007

Corolla herbivory, pollination success and fruit predation in complex flowers: an experimental study with Linaria lilacina (Scrophulariaceae).

BACKGROUND AND AIMS: Herbivory on floral structures has been postulated to influence the evolution of floral traits in some plant species, and may also be an important factor influencing the occurrence and outcome of subsequent biotic interactions related to floral display. In particular, corolla herbivory may affect structures differentially involved in flower selection by pollinators and fruit predators (specifically, those ovopositing in ovaries prior to fruit development); hence floral herbivores may influence the relationships between these mutualistic and antagonistic agents. METHODS: The effects of corolla herbivory in Linaria lilacina (Scrophulariaceae), a plant species with complex flowers, were considered in relation to plant interactions with pollinators and fruit predators. Tests were made as to whether experimentally created differences in flower structure (resembling those occurring naturally) may translate into differences in reproductive output in terms of fruit or seed production. KEY RESULTS: Flowers with modified corollas, particularly those with lower lips removed, were less likely to be selected by pollinators than control flowers, and were less likely to be successfully visited and pollinated. As a consequence, fruit production was also less likely in these modified flowers. However, none of the experimental treatments affected the likelihood of visitation by fruit predators. CONCLUSIONS: Since floral herbivory may affect pollinator visitation rates and reduce seed production, differences among plants in the proportion of flowers affected by herbivory and in the intensity of the damage inflicted on affected flowers may result in different opportunities for reproduction for plants in different seasons.

Animals↗
PubMed1990

Piroxicam may reduce the rate of progression of experimental diabetic neuropathy.

We studied the effect of piroxicam, a long acting inhibitor of platelet aggregation, on the evolution of neuropathy in diabetic rats. We treated half of the rats with piroxicam and serially studied sensory and motor nerve conduction during 20 weeks of diabetes. The sensory nerve action potential amplitude was the same in treated and untreated rats before diabetes, and declined steadily as duration of diabetes increased. In treated rats, the amplitude fell more slowly and by 16 weeks and thereafter was significantly higher than in untreated rats. Sensory conduction velocity and motor nerve conduction studies were not affected by piroxicam treatment. The results suggest that piroxicam may slow the rate of progression of neuropathy in diabetic rats, probably by inhibiting platelet aggregation.

Action Potentials↗
PubMed2001

[Impact of age on pain perception and analgesic pharmacology].

INFLUENCE OF AGING ON PAIN: Although pain affects a large majority of the elderly population living in the community and in institutions, our knowledge of the evolution of pain experience with age is poor. Results of clinical surveys and experimental pain studies are contradictory, showing no change, an increase, or a decrease of pain with age. Many results suggest a decrease of pain perception with age that could be explained by peripheral and central neuroanatomical aging and psychological changes of the aging patient towards pain. INFLUENCE OF AGE ON THE PHARMACOLOGY OF ANALGESICS: Biological aging added to multiple pathologies and polymedication explains the pharmacological changes of analgesics. Among pharmacokinetic changes that are globally well known, vigilance must focus on renal excretion of analgesics and their metabolites and on the increased risk of side-effects and drug interactions. Information on pharmacodynamic changes of analgesics are scarce in aging patients who are susceptible to drugs and which demographical trend increases. PERSPECTIVES: A better fundamental knowledge of the evolution of pain with age could help to improve care in the elderly with pain, especially in very old subjects with cognitive impairment and loss of communication skills, where pain evaluation is particularly difficult. Also, more research is needed on the pharmacodynamics of analgesics in older subjects, with a view of a decreased iatrogenic risk, a better pain treatment and quality of life of the elderly.

Age Factors↗
PubMed1993

On the formulation and computer implementation of an age-dependent two-sex demographic model.

A two-sex age-dependent demographic model is formulated within the framework of a stochastic population process, including both time-homogeneous and time-inhomogeneous laws of evolution. An outline of the parametric components of the system, which expedite computer implementation and experimentation, is also given. New features of the model include a component for couple formation, using the class of Farlie-Morgenstern bivariate distributions to accommodate age preferences in selecting marriage partners, a component for couple dissolution due to separation or divorce, and an outline of techniques for initializing a two-sex projection given scanty information. For the case of time-homogeneous laws of evolution, stability properties of two-sex models that are analogs of those for one-sex models are difficult to prove mathematically due to nonlinearities. But computer experiments in this case suggest that these properties continue to hold for two-sex models for such widely used demographic indicators as period crude birth rates, period rates of natural increase, and period age distributions, which converge to constant forms in long-term projections. The values of the stable crude birth rate, rate of natural increase, and quantiles of the stable age distribution differ markedly among projections that differ only in selected values of parameters governing couple formation and dissolution. Such experimental results demonstrate that two-sex models are not merely intellectual curiosities but exist in their own right and lead to insights not attainable in simpler one-sex formulations.

Age Factors↗
PubMedDate not supplied

Empirical and mechanistic mathematical models of temporal evolution of milk production in ruminants.

In the various sectors of animal science there has been little exploration of the theoretical mathematical aspects of data analysis and modelling. The dominant statistical methods used for the analysis of experimental data are rarely valuable for developing a deeper understanding of the problem. In addition they do not take account of the evolution over time of those variables of major interest to be studied. Only recently have more sophisticated methods of mathematical modelling begun to be used. Nonetheless attention tends to be focused exclusively on empirical models. Mathematical models with greater explanatory power, in particular those which use differential equations, are as yet little used. This work develops a mathematical approach to a problem that is of great interest in animal science: the development over time of milk production in economically important ruminant species.

Animals↗
PubMed2004

Role of interleukin-18 in experimental group B streptococcal arthritis.

OBJECTIVE: To assess the role of interleukin-18 (IL-18) in the evolution of septic arthritis induced by group B streptococci (GBS) in mice. METHODS: CD1 mice were inoculated intravenously with 8 x 10(6) colony-forming units (CFU) of type IV GBS (strain 1/82), and administered intraperitoneally 1 hour before infection with anti-IL-18 monoclonal antibodies (0.25 mg/mouse). In a subsequent set of experiments, mice infected with a suboptimal arthritogenic dose of GBS (4 x 10(6) CFU/mouse) were administered different doses of recombinant IL-18 for 4 days, starting 1 hour after infection. Mortality, evolution of arthritis, bacterial clearance, joint histopathology, and cytokine production were examined in infected mice that did or did not receive treatment with anti-IL-18 antibodies or IL-18. RESULTS: IL-18 was produced during GBS infection. Neutralization of IL-18 resulted in a decrease in mortality rates, and in the incidence and severity of arthritis. Amelioration of arthritis was accompanied by a dramatic reduction in local IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-2 production, and reduced bacterial burden. Administration of exogenous IL-18 resulted in increased mortality rates and increased incidence and severity of GBS arthritis, concomitant with a higher number of GBS and increased levels of IL-6, IL-1 beta, MIP-1 beta, and MIP-2 production in the joints. CONCLUSION: The present study indicated some involvement of IL-18 in the pathogenesis of GBS-induced arthritis. The role of IL-18 in joint pathology is shown by a regulatory effect on inflammatory mediator levels and local cell influx. Thus, IL-18 should be regarded as a potential therapeutic target in GBS infection and arthritis.

Animals↗
PubMed2001

Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach.

We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient's tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp(6)-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp(6)-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism.

Animals↗
PubMed2003

Information transfer about roosts in female Bechstein's bats: an experimental field study.

Information transfer among group members is believed to play an important part in the evolution of coloniality in both birds and bats. Although information transfer has received much scientific interest, field studies using experiments to test the underlying hypotheses are rare. We used a field experiment to test if communally breeding female Bechstein's bats (Myotis bechsteinii) exchange information regarding novel roosts. We supplied a wild colony, comprising 17 adult females of known relatedness, with pairs of suitable and unsuitable roosts and monitored the arrival of individuals marked with transponders (PIT-tags) over 2 years. As expected with information transfer, significantly more naive females were recruited towards suitable than towards unsuitable roosts. We conclude that information transfer about roosts has two functions: (i) it generates communal knowledge of a large set of roosts; and (ii) it aids avoidance of colony fission during roost switching. Both functions seem important in Bechstein's bats, in which colonies depend on many day roosts and where colony members live together for many years.

Animal Communication↗