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1.
Science ; 248(4951): 83-5, 1990 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-2321028

RESUMEN

Neurons with oscillatory properties are a common feature of the nervous system, but little is known about how neural oscillators shape the behavior of neuronal networks or how network interactions influence the properties of neural oscillators. Mathematical models are used to examine the effect of electrically coupling an oscillatory neuron to a second neuron that is either silent or tonically firing. Models of oscillatory neurons with varying degrees of complexity show that this coupling can either increase or decrease the frequency of an oscillator, depending on its membrane potential wave form, the state of the neuron to which it is coupled, and the strength of the coupling. Thus, electrical coupling provides a flexible mechanism for modifying the behavior of an oscillatory neural network.


Asunto(s)
Modelos Biológicos , Neuronas/fisiología , Potenciales de Acción , Relojes Biológicos , Conductividad Eléctrica , Electrofisiología , Matemática , Potenciales de la Membrana
2.
Curr Opin Genet Dev ; 11(6): 612-5, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11682302

RESUMEN

Several lines of research are now converging towards an integrated understanding of mutational mechanisms and their evolutionary implications. Experimentally, crystal structures reveal the effect of sequence context on polymerase fidelity; large-scale sequencing projects generate vast amounts of sequence polymorphism data; and locus-specific databases are being constructed. Computationally, software and analytical tools have been developed to analyze mutational data, to identify mutational hot spots, and to compare the signatures of mutagenic agents.


Asunto(s)
Biología Computacional/tendencias , Mutación , Análisis de Secuencia de ADN/normas , Estadística como Asunto , Bases de Datos Factuales , Variación Genética , Genoma Humano , Humanos , Datos de Secuencia Molecular
3.
J Clin Invest ; 103(6): 833-41, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10079104

RESUMEN

Template-independent nucleotide additions (N regions) generated at sites of V(D)J recombination by terminal deoxynucleotidyl transferase (TdT) increase the diversity of antigen receptors. Two inborn errors of purine metabolism, deficiencies of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), result in defective lymphoid development and aberrant pools of 2'-deoxynucleotides that are substrates for TdT in lymphoid precursors. We have asked whether selective increases in dATP or dGTP pools result in altered N regions in an extrachromosomal substrate transfected into T-cell or pre-B-cell lines. Exposure of the transfected cells to 2'-deoxyadenosine and an ADA inhibitor increased the dATP pool and resulted in a marked increase in A-T insertions at recombination junctions, with an overall decreased frequency of V(D)J recombination. Sequence analysis of VH-DH-JH junctions from the IgM locus in B-cell lines from ADA-deficient patients demonstrated an increase in A-T insertions equivalent to that found in the transfected cells. In contrast, elevation of dGTP pools, as would occur in PNP deficiency, did not alter the already rich G-C content of N regions. We conclude that the frequency of V(D)J recombination and the composition of N-insertions are influenced by increases in dATP levels, potentially leading to alterations in antigen receptors and aberrant lymphoid development. Alterations in N-region insertions may contribute to the B-cell dysfunction associated with ADA deficiency.


Asunto(s)
Adenosina Desaminasa/deficiencia , ADN Nucleotidilexotransferasa/metabolismo , Desoxirribonucleótidos/metabolismo , Errores Innatos del Metabolismo de la Purina-Pirimidina/enzimología , Recombinación Genética , Inhibidores de la Adenosina Desaminasa , Adenosina Trifosfato/metabolismo , Células Cultivadas , Desoxiadenosinas/farmacología , Nucleótidos de Desoxiguanina/metabolismo , Reordenamiento Génico de Linfocito B , Humanos , Inmunoglobulina M/genética , Análisis de Secuencia de ADN
4.
Mucosal Immunol ; 8(2): 316-26, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25100291

RESUMEN

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Calostro/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Lactancia , Negro o Afroamericano , Formación de Anticuerpos/inmunología , Linfocitos B/citología , Recuento de Linfocito CD4 , Evolución Clonal , Calostro/citología , Regiones Determinantes de Complementariedad/genética , Epítopos de Linfocito B/inmunología , Femenino , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Memoria Inmunológica , Inmunofenotipificación , Transmisión Vertical de Enfermedad Infecciosa , Tasa de Mutación , Fenotipo , Hipermutación Somática de Inmunoglobulina , Carga Viral
5.
AIDS Res Hum Retroviruses ; 15(13): 1219-28, 1999 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-10480635

RESUMEN

HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.


Asunto(s)
Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Estudios Transversales , Pruebas Inmunológicas de Citotoxicidad , Productos del Gen pol/genética , Productos del Gen pol/metabolismo , Infecciones por VIH/virología , VIH-1/fisiología , Antígenos de Histocompatibilidad Clase I/clasificación , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Estudios Longitudinales , Masculino , Receptores CCR5/genética , Carga Viral
6.
Shock ; 16(4): 248-51, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11580104

RESUMEN

For the past century, students of shock have focused research efforts to illuminate specific mechanisms that cause, or fail as a consequence of, circulatory collapse. Although clinical strategies aimed at supporting or restoring individual organ systems have proven effective, many patients succumb to more generalized multiple organ system failure. We suggest that general biological systems failure cannot be interpreted through reliance on reductionist science. We propose that complex systems analysis is an essential tool for shock research and we evaluate its application to genomic technologies.


Asunto(s)
Biología Molecular/métodos , Choque/fisiopatología , Animales , Fenómenos Fisiológicos Celulares , Regulación de la Expresión Génica , Humanos , Biología Molecular/tendencias , Investigación , Choque/metabolismo , Choque/patología , Transducción de Señal
7.
Toxicol Sci ; 53(2): 173-84, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10696765

RESUMEN

Phthalate esters are ubiquitous, low-level environmental contaminants that induce testicular toxicity in laboratory animals. The diester is rapidly metabolized in the gut to the monoester, which causes the testicular toxicity. Several physiologically based pharmacokinetic (PBPK) model structures have been evaluated for di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP). The objective of this study was to test these PBPK models for a less lipophilic phthalate diester, di(n-butyl) phthalate (DBP), and monoester, mono(n-butyl) phthalate (MBP). Alternate models describing enterohepatic circulation, diffusion-limitation, tissue pH gradients (pH trapping), and a simpler, flow-limited model were evaluated. A combined diffusion-limited and pH trapping model was also tested. MBP tissue:blood partition coefficients were similar when determined either experimentally by a nonvolatile, vial equilibration technique or algorithmically. All other parameters were obtained from the literature or estimated from MBP blood concentrations following intravenous or oral exposure to DBP or MBP. A flow-limited model was unable to predict MBP blood levels, whereas each alternative model had statistically better predictions. The combined diffusion-limited and pH trapping model was the best overall, having the highest log-likelihood function value. This result is consistent with a previous finding that the pH trapping model was the best model for describing DEHP and MEHP blood dosimetry, though it was necessary to extend the model to include diffusion-limitation. The application of the pH trapping model is a step toward developing a generic model structure for all phthalate esters, though more work is required before a generic structure can be identified with confidence. Development of a PBPK model structure applicable to all phthalate esters would support more realistic assessments of risk to human health from exposure to one or more members of this class of compounds.


Asunto(s)
Dibutil Ftalato/farmacocinética , Ácidos Ftálicos/farmacocinética , Administración Oral , Animales , Dibutil Ftalato/análisis , Contaminantes Ambientales/sangre , Contaminantes Ambientales/farmacocinética , Inyecciones Intravenosas , Masculino , Modelos Biológicos , Ácidos Ftálicos/sangre , Ratas , Ratas Sprague-Dawley , Ratas Wistar
8.
Toxicol Sci ; 49(2): 172-85, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10416263

RESUMEN

Di(2-ethylhexyl) phthalate (DEHP), a commercially important plasticizer, induces testicular toxicity in laboratory animals at high doses. After oral exposure, most of the DEHP is rapidly metabolized in the gut to mono(2-ethylhexyl) phthalate (MEHP), which is the active metabolite for induction of testicular toxicity. To quantify the testes dose of MEHP with various routes of exposure and dose levels, we developed a physiologically based pharmacokinetic (PBPK) model for DEHP and MEHP in rats. Tissue:blood partition coefficients for DEHP were estimated from the n-octanol: water partition coefficient, while partition coefficients for MEHP were determined experimentally using a vial equilibration technique. All other parameters were either found in the literature or estimated from blood or tissue levels following oral or intravenous exposure to DEHP or MEHP. A flow-limited model failed to adequately simulate the available data. Alternative plausible mechanisms were explored, including diffusion-limited membrane transport, enterohepatic circulation, and MEHP ionization (pH-trapping model). In the pH-trapping model, only nonionized MEHP is free to become partitioned into the tissues, where it is equilibrated and trapped as ionized MEHP until it is deionized and released. All three alternative models significantly improved predictions of DEHP and MEHP blood concentrations over the flow-limited model predictions. The pH-trapping model gave the best predictions with the largest value of the log likelihood function. Predicted MEHP blood and testes concentrations were compared to measured concentrations in juvenile rats to validate the pH-trapping model. Thus, MEHP ionization may be an important mechanism of MEHP blood and testes disposition in rats.


Asunto(s)
Ácidos Ftálicos/sangre , Ácidos Ftálicos/farmacocinética , Plastificantes/metabolismo , Testículo/metabolismo , Animales , Difusión , Circulación Enterohepática/fisiología , Concentración de Iones de Hidrógeno , Masculino , Modelos Biológicos , Ratas , Ratas Sprague-Dawley , Solubilidad
9.
Math Biosci ; 170(1): 59-77, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11259803

RESUMEN

The germinal center reaction (GCR) of vertebrate immunity provides a remarkable example of evolutionary succession, in which an advantageous phenotype arises as a spontaneous mutation from the parental type and eventually displaces the parental type altogether. In the case of the immune response to the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP), as with several other designed immunogens, the process is dominated by a single key mutation, which greatly simplifies the modeling of and analysis of data. We developed a two-stage model of this process in which the primary stage represents the appearance and establishment of the mutant population as a stochastic process while the second stage represents the growth and dominance of the clone as a deterministic process, conditional on its time of establishment from stage one. We applied this model to the analysis of population samples from several germinal center (GC) reactions and used maximum-likelihood methods to estimate the waiting times to arrival and to dominance of the mutant clone. We determined the sampling properties of the maximum-likelihood estimates using Monte Carlo methods and compared them to their asymptotic distributions. The methods we present here are well-suited for use in the analysis of other systems, such as tumor growth and the experimental evolution of bacteria.


Asunto(s)
Centro Germinal/inmunología , Modelos Genéticos , Mutación/genética , Selección Genética , Vertebrados/genética , Animales , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Simulación por Computador , Genes Dominantes , Funciones de Verosimilitud , Método de Montecarlo , Mutación/inmunología , Nitrofenoles/inmunología , Fenilacetatos , Procesos Estocásticos , Vertebrados/inmunología
11.
J Mol Biol ; 379(4): 912-28, 2008 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-18482736

RESUMEN

The genome of the purple sea urchin contains numerous large gene families with putative immunological functions. One gene family, known as 185/333, is characterized by extraordinary molecular diversity resulting from single nucleotide polymorphisms and the presence or the absence of 27 large blocks of sequences known as elements. The mosaic composition of elements, known as element patterns, that is present within the members of this gene family is encoded entirely in the second of two exons. Many of the elements correspond to one of six types of repeats that are present throughout the genes. The sequence diversity and variation in element patterns led us to investigate the evolution of the 185/333 gene family. The work presented here suggests that the element patterns are the result of both recombination and duplication and/or deletion of intragenic repeats. Each element is composed of a limited number of similar but distinct sequences, and their distribution among the 185/333 genes suggests frequent recombination within this gene family. Phylogenetic analyses of five 185/333 elements and two regions of the intron were performed using two tests: incongruence length difference and incongruence permutation. Results indicated that each pair of sequence segments was incongruent, suggesting that recombination occurs frequently along the length of the genes, including both the intron and the second exon, and that recombination is not restricted to intact elements. Paradoxically, the high level of similarity among the elements indicated that the 185/333 genes appear to be the result of a recent diversification. These results add to the growing body of evidence suggesting that invertebrate immune systems are not simple and static, but are dynamic and highly complex, and may employ group-specific mechanisms for diversification.


Asunto(s)
Familia de Multigenes , Strongylocentrotus purpuratus/genética , Strongylocentrotus purpuratus/inmunología , Animales , Secuencia de Bases , ADN/genética , Evolución Molecular , Exones , Duplicación de Gen , Variación Genética , Inmunidad Innata/genética , Intrones , Datos de Secuencia Molecular , Filogenia , Polimorfismo de Nucleótido Simple , Recombinación Genética , Secuencias Repetitivas de Ácidos Nucleicos , Eliminación de Secuencia , Homología de Secuencia de Ácido Nucleico
12.
Osteoarthritis Cartilage ; 14(8): 723-7, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16733093

RESUMEN

OBJECTIVE: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for OA are developed and tested in clinical studies, biomarkers that reliably mirror or predict the progression or amelioration of OA will also be needed. METHODS: The NIH-funded OA Biomarkers Network is a multidisciplinary group interested in the development and validation of OA biomarkers. This review summarizes our efforts to characterize and classify OA biomarkers. RESULTS: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in OA investigations. CONCLUSION: The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework.


Asunto(s)
Osteoartritis/clasificación , Reumatología , Artrografía , Biomarcadores/análisis , Progresión de la Enfermedad , Humanos , Oportunidad Relativa , Osteoartritis/diagnóstico por imagen , Osteoartritis/terapia , Pronóstico , Factores de Riesgo , Resultado del Tratamiento
13.
Mol Biol Evol ; 14(6): 637-43, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9190065

RESUMEN

Immunoglobulin genes experience Darwinian evolution twice. In addition to the germline evolution all genes experience, immunoglobulins are subjected, upon exposure to antigen, to somatic hypermutation. This is accompanied by selection for high affinity to the eliciting antigen and frequently results in a significant increase in the specificity of the responding population. The hypermutation mechanism displays a strong sequence specificity. Thus arises the opportunity to manipulate codon bias in a site-specific manner so as to direct hypermutation to those parts of the gene that encode the antigen-binding portions of the molecule and away from those that encode the structurally conserved regions. This segregation of mutability would clearly be advantageous; it would enhance the generation of potentially useful variants while keeping mutational loss to acceptably low levels. But it is not clear that the advantage gained would be large enough to produce a measurable effect within the background stochasticity of the evolutionary process. I have performed a pair of statistical tests to determine whether site-specific codon bias in human immunoglobulin genes is correlated with the sequence specificity of the somatic mutation mechanism. The sequence specificity of the mutator was determined by analysis of a database of published immunoglobulin intron sequences that had experienced somatic mutation but not selection. The site-specific codon bias was determined by analysis of published sequences of human germline immunoglobulin V genes. Both tests strongly suggest that evolution has acted to enhance the plasticity of immunoglobulin genes under somatic hypermutation.


Asunto(s)
Codón , Variación Genética , Inmunoglobulinas/fisiología , Modelos Genéticos , Mutación , Aminoácidos/genética , Sitios de Unión , Humanos , Región Variable de Inmunoglobulina/genética , Modelos Lineales , Datos de Secuencia Molecular , Selección Genética , Alineación de Secuencia
14.
J Immunol ; 164(4): 1971-6, 2000 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-10657647

RESUMEN

Somatic mutation is a fundamental component of acquired immunity. Although its molecular basis remains undetermined, the sequence specificity with which mutations are introduced has provided clues to the mechanism. We have analyzed data representing over 1700 unselected mutations in V gene introns and nonproductively rearranged V genes to identify the sequence specificity of the mutation spectrum-the distribution of resultant nucleotides. In other words, we sought to determine what effects the neighboring bases have on what a given base mutates "to." We find that both neighboring bases have a significant effect on the mutation spectrum. Their influences are complicated, but much of the effect can be characterized as enhancing homogeneity of the mutated DNA sequence. In contrast to what has been reported for the sequence specificity of the "targeting" mechanism, that of the spectrum is notably symmetric under complementation, indicating little if any strand bias. We compared the spectrum to that found previously for germline mutations as revealed by analyzing pseudogene sequences. We find that the influences of nearest neighbors are quite different in the two datasets. Altogether, our findings suggest that the mechanism of somatic hypermutation is complex, involving two or more stages: introduction of mis-pairs and their subsequent resolution, each with distinct sequence specificity and strand bias.


Asunto(s)
Mutación de Línea Germinal/inmunología , Nucleótidos/inmunología , Adenina/inmunología , Animales , Composición de Base , Secuencia de Bases , Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/estadística & datos numéricos , Reordenamiento Génico , Humanos , Región Variable de Inmunoglobulina/genética , Ratones , Nucleótidos/genética , Seudogenes/inmunología , Timina/inmunología
15.
Biol Cybern ; 68(3): 209-14, 1993.
Artículo en Inglés | MEDLINE | ID: mdl-8452888

RESUMEN

We investigate spike initiation and propagation in a model axon that has a slow regenerative conductance as well as the usual Hodgkin-Huxley type sodium and potassium conductances. We study the role of slow conductance in producing repetitive firing, compute the dispersion relation for an axon with an additional slow conductance, and show that under appropriate conditions such an axon can produce a traveling zone of secondary spike initiation. This study illustrates some of the complex dynamics shown by excitable membranes with fast and slow conductances.


Asunto(s)
Axones/fisiología , Potenciales de Acción/fisiología , Animales , Cibernética , Conductividad Eléctrica , Estimulación Eléctrica , Electrofisiología , Modelos Neurológicos
16.
Theor Popul Biol ; 59(1): 41-8, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11243927

RESUMEN

The estimation of mutation rates is ordinarily performed using results based on the Luria-Delbrück distribution. There are certain difficulties associated with the use of this distribution in practice, some of which we address in this paper (others in the companion paper, Oprea and Kepler, Theor. Popul. Biol., 2001). The distribution is difficult to compute exactly, especially for large values of the random variable. To overcome this problem, we derive an integral representation of the Luria-Delbrück distribution that can be computed easily for large culture sizes. In addition, we introduce the usual assumption of very small probability of having a large proportion of mutants only after the generating function has been computed. Thus, we obtain information on the moments for the more general case. We examine the asymptotic behavior of this system. We find a scaling or "standardization" technique that reduces the family of distributions parameterized by three parameters (mutation rate, initial cell number, and final cell number) to a single distribution with no parameters, valid so long as the product of the mutation rate and the final culture is sufficiently large. We provide a pair of techniques for computing confidence intervals for the mutation rate. In the second paper of this series, we use the distribution derived here to find approximate distributions for the case where the cell cycle time is not well-described as an exponential random variable as is implicitly assumed by Luria-Delbrück distribution.


Asunto(s)
Interpretación Estadística de Datos , Modelos Genéticos , Mutación/genética , Distribuciones Estadísticas , Ciclo Celular/genética , Intervalos de Confianza , Cadenas de Markov
17.
Theor Popul Biol ; 59(1): 49-59, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11243928

RESUMEN

In the first paper of this series (Kepler and Oprea, Theor. Popul. Biol. 2001) we found a continuum approximation of the Luria-Delbrück distribution in terms of a scaled variable related to the proportion of mutants in the culture. Here we show that the Luria-Delbrück distribution is inaccurate when realistic division processes are being considered due to the non-Markovian character of the cell cycle. We derive the expectation of the proportion of mutants in the culture for arbitrary cell-cycle time distributions. We then introduce a two-parameter generalization of the continuum Luria-Delbrück distribution for two of the more commonly used cell-cycle time distributions: gamma and shifted exponential. We obtain the generalized distribution by defining a map from the actual parameters to "effective" parameters. The effective mutation rate is obtained analytically, while the effective population size is obtained by fitting simulation data. Our simulations show that the second parameter depend mostly on the coefficient of variation of the cell-cycle time distribution.


Asunto(s)
Ciclo Celular/genética , Interpretación Estadística de Datos , Modelos Genéticos , Mutación/genética , Distribuciones Estadísticas , Algoritmos , Sesgo , Intervalos de Confianza , Genética de Población , Fenotipo , Filogenia , Densidad de Población , Factores de Tiempo
18.
Biophys J ; 81(6): 3116-36, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11720979

RESUMEN

Transcriptional regulation is an inherently noisy process. The origins of this stochastic behavior can be traced to the random transitions among the discrete chemical states of operators that control the transcription rate and to finite number fluctuations in the biochemical reactions for the synthesis and degradation of transcripts. We develop stochastic models to which these random reactions are intrinsic and a series of simpler models derived explicitly from the first as approximations in different parameter regimes. This innate stochasticity can have both a quantitative and qualitative impact on the behavior of gene-regulatory networks. We introduce a natural generalization of deterministic bifurcations for classification of stochastic systems and show that simple noisy genetic switches have rich bifurcation structures; among them, bifurcations driven solely by changing the rate of operator fluctuations even as the underlying deterministic system remains unchanged. We find stochastic bistability where the deterministic equations predict monostability and vice-versa. We derive and solve equations for the mean waiting times for spontaneous transitions between quasistable states in these switches.


Asunto(s)
Regulación de la Expresión Génica , Procesos Estocásticos , Transcripción Genética , Retroalimentación Fisiológica , Modelos Teóricos , Método de Montecarlo , Regiones Promotoras Genéticas , Factores de Tiempo
19.
J Theor Biol ; 164(1): 37-64, 1993 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-8264243

RESUMEN

The vertebrate immune system generates high-affinity antibodies to external antigens through a process of somatic hypermutation that takes place in germinal centers formed in the secondary lymphoid tissues. B cells proliferating in these germinal centers experience random mutations in the genes encoding the variable region of their immunoglobulin molecules and are subsequently selected for high-affinity binding to antigen. These germinal center reactions last for only about 2 weeks, yet in that time typically produce multiple point mutations resulting in affinity increases of factors of ten to a hundred or more. We have attempted to understand this extraordinary effectiveness by causing the problem of affinity maturation as an optimization problem in which a quantity that we call the total affinity is maximized as a functional of mu(t), the mutation rate as a function of time. We have developed a single-compartment model for the process and an optimization algorithm based on the Pontryagin maximum principle. Our results show that the optimum mutation schedule is one with brief bursts of high mutation rates interspersed between periods of mutation-free growth. Though this result at first seems highly non-physiological, we show that, in fact, it provides a framework within which the anatomy and kinetics of the germinal center reaction can be understood.


Asunto(s)
Linfocitos B/inmunología , Activación de Linfocitos/genética , Modelos Genéticos , Mutación/inmunología , Animales , Afinidad de Anticuerpos/genética , Antígenos/inmunología , División Celular/inmunología , Región Variable de Inmunoglobulina/genética , Cinética , Matemática , Vertebrados/genética
20.
Immunol Today ; 14(8): 412-5, 1993 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8397781

RESUMEN

Affinity maturation of the humoral immune response by somatic hypermutation is marked by a rapid and dramatic increase in affinity for the eliciting antigen. We suggest that the optimal mutation schedule is one in which periods of rapid mutation alternate with periods of mutation-free growth. The multicompartmental structure of the germinal center, together with re-entry of positively selected B cells back into the germinal center, will naturally implement such a schedule, thereby providing an anatomical basis for the efficiency of the germinal center reaction.


Asunto(s)
Linfocitos B/inmunología , Células Germinativas/inmunología , Región Variable de Inmunoglobulina/genética , Matemática , Mutación
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